Therapeutic agent for motor disorders

ABSTRACT

Provided are an agent for the treatment and/or prophylaxis of a movement disorder, the agent for the treatment and/or prophylaxis wherein the movement disorder is extrapyramidal syndrome, the agent for the treatment and/or prophylaxis wherein the movement disorder is bradykinesia, gait disturbance, dystonia, dyskinesia or tardive dyskinesia, the agent for the treatment and/or prophylaxis wherein the movement disorder is a side effect of L-DOPA and/or dopamine agonist therapy, and the like, each containing a thiazole derivative represented by the formula (I) wherein R 1  represents aryl and the like, and R 2  represents pyridyl or the like, or a pharmaceutically acceptable salt thereof as an active ingredient.

TECHNICAL FIELD

The present invention relates to an agent for the treatment and/orprophylaxis of a movement disorder, an agent for the treatment and/orprophylaxis of Parkinson's disease and the like.

BACKGROUND ART

Parkinson's disease is a brain disease characterized by tremor,bradykinesia, difficulty in gait and coordinated movement and the like.This disease is associated with damage of a part of brain which governsmuscle movements. Generally, the first symptom of Parkinson's disease isa limb tremor (shaking or trembling) particularly when the body is atrest. Tremor often begins in the hemibody, and frequently occurs in oneof the hands. Other common symptoms include slow movement(bradykinesia), an inability to move (akinesia), a rigidity of trunk andlimbs, a shuffling gait, and a stooped posture and the like. Patientswith Parkinson's disease are poor in facial expression, and tend tospeak in a soft voice. Parkinson's disease can cause secondary symptomssuch as depression, anxiety, personality change, cognitive impairment,dementia, sleep disturbances, speech impairments or sexual dysfunction.The drug therapy of Parkinson's disease currently employed clinicallymainly controls the parkinsonian symptoms by controlling the imbalanceamong neurotransmitters. Early stage patients of Parkinson's diseasemostly respond well to a symptomatic therapy by a dopamine replacementtherapy; however, the disability increases with progression of thedisease.

Although currently available medications for Parkinson's diseasegenerally provide adequate symptomatic control for several years,however, many patients develop motor fluctuations and dyskinesias thatcompromise clinical response (The New England Journal of Medicine (N.Eng. J. Med.), vol. 342, p. 1484 (2000) and the like).

Although more than thirty years have passed since discovering L-DOPA, itis still the best agent for treatment of Parkinson's disease. In theearly stages of Parkinson's disease, patients usually enjoy a goodresponse to L-DOPA. As the disease progresses, however, L-DOPA tends tobecome less helpful. This is not due to the loss of efficacy of L-DOPA,but rather, for example, to development of motor complications such asend-of-dose deterioration or adverse fluctuation in motor responseincluding “wearing-off phenomenon”, “on-off fluctuations”, anddyskinesias.

The “on-off fluctuations” is an event wherein therapeutic benefit of amedication (“on” state, during which the patients are relatively freefrom the symptoms of Parkinson's disease) is suddenly and unacceptablylost, and the parkinsonian state (“off” state) appears. Such conditionoccurs when patients with Parkinson's disease are under L-DOPA therapyand exposed to L-DOPA in an amount sufficient to express the efficacy.However, even if such symptoms are expressed, the treatment effect mayrecover all of a sudden.

The “wearing-off phenomenon” is a phenomenon wherein the duration ofL-DOPA action is decreased in patients with Parkinson's disease, eventhough they are under L-DOPA therapy and exposed to L-DOPA in an amountsufficient to express the efficacy. The phenomenon is characterized bythe gradual reappearance of the “off” state, and shortening of the “on”state. That is, it refers to a phenomenon where the duration of thetreatment effect of L-DOPA gradually becomes shorter (duration of thetreatment effect after administration of L-DOPA becomes shorter), whichis remarkably seen in an advanced stage of the disease in patients withParkinson's disease under L-DOPA therapy.

Dyskinesia can be broadly classified into chorea-like symptoms(hyperactive, purposeless dance-like movement) and dystonia (sustained,abnormal muscle contraction). In 1974, Duvoisin first focused on theseabnormal involuntary movements, and found that half or more of patientswith Parkinson's disease develop dyskinesia within 6 months of thetreatment. With increasing period of treatment, both the frequency andseverity of dyskinesia increase. In a study of the potential benefits ofpossible neuroprotectants in Parkinson's disease—DATATOP trial—, L-DOPAinduced dyskinesia was observed in 20-30% of patients who receivedL-DOPA treatment for a mean of 20.5 months. Ultimately, most L-DOPAtreated patients experienced dyskinesia; up to 80% of the patientsdeveloped dyskinesia within 5 years. (Annals of Neurology (Ann.Neurol.), vol. 39, p. 37 (1966); The New England Journal of Medicine (N.Eng. J. Med.), vol. 342, p. 1484 (2000)). Most dyskinesias occur whenL-DOPA or other dopamine receptor agonists have a concentration in thebrain that is sufficient to hypersensitive dopamine receptors in theputamen (peak dose dyskinesia). However, dyskinesia also occurs when thedopamine concentration is low (off-dystonia), or in a stage wherein theconcentration of dopamine rises or falls (biphasic dyskinesia).

On the other hand, it is known that adenosine is widely distributed inthe whole body, and exhibits a variety of physiological actions on thecentral nervous system, the cardiac muscle, the kidneys, the smoothmuscle, and the like through its receptors (see non-patent document 1),and that an antagonist thereof is useful for the treatment and/orprophylaxis of various diseases.

For example, adenosine A₁ antagonists are known to facilitate defecation(The Japanese Journal of Pharmacology (Jpn. J. Pharmacol.), Vol. 68, p.119 (1995)). Further, the adenosine A_(2A) receptors are known to beinvolved particularly in the central nervous system, and the antagonistsof the adenosine A_(2A) receptors are known to be useful as, forexample, therapeutic drugs for Parkinson's disease etc. (see non-patentdocument 2), therapeutic drugs for sleep disturbance (see NatureNeuroscience, p. 858 (2005); patent document 1) and the like. There aremany reports concerning the relationship between adenosine receptors andParkinson's disease (see, for example, non-patent documents 3 and 4).

In addition, (i) a method of reducing or suppressing side effects ofL-DOPA therapy, (ii) a treatment method by reducing the dose of L-DOPAin L-DOPA therapy, (iii) a method of prolonging the duration ofeffectiveness of the treatment of Parkinson's disease in L-DOPA therapy,(iv) a method of treating a movement disorder and the like, each usingan adenosine A_(2A) receptor antagonist, are known (see patent document2). To be specific, it is known that movement disorders such as tremor,bradykinesia, gait disturbance, akinesia and the like can be suppressedby administering an adenosine A_(2A) receptor antagonist represented bythe formula (A) and L-DOPA to patients with Parkinson's disease, andadenosine A_(2A) receptor antagonist represented by the formula (A)suppresses dyskinesia developed by administration of L-DOPA, and thelike. Furthermore, it is known that an adenosine A_(2A) receptorantagonist represented by the formula (A) shows an antiparkinson effectin MPTP-treated common marmoset (see non-patent document 5), does notprovoke dyskinesia (see non-patent document 6), and does not provokedyskinesia but potentiates an antiparkinson effect when used incombination with L-DOPA and/or a dopamine agonist (see non-patentdocument 7).

On the other hand, for example, compounds represented by the formulas(IA), (IB), (IC), (ID) and the like are known to have affinity toadenosine A_(2A) receptors and have a therapeutic effect for Parkinson'sdisease (see patent document 3). Moreover, thiazole derivatives havingan adenosine A_(2A) receptor antagonistic activity are known (see patentdocument 4). It is also known that these compounds are useful as anagent for the treatment and/or prophylaxis of sleep disturbance (seepatent document 1), an agent for the treatment and/or prophylaxis ofmigraine (see patent document 5), an analgesic tolerance inhibitor (seepatent document 6) and the like.

PRIOR DOCUMENT LIST Patent Documents

-   [patent document 1] WO2007/015528-   [patent document 2] WO2003/063876-   [patent document 3] WO2005/063743-   [patent document 4] WO2006/137527-   [patent document 5] WO2010/010908-   [patent document 6] WO2009/145289

Non-Patent Documents

-   [non-patent document 1] Nature Reviews Drug Discovery, 2006, vol.    5, p. 247-   [non-patent document 2] Progress in Neurobiology, 2007, vol. 83, p.    332-   [non-patent document 3] Nature Reviews Drug Discovery, 2006, vol.    5, p. 845-   [non-patent document 4] Current Pharmaceutical Design, 2008, vol.    14, p. 1475-   [non-patent document 5] Neurology, 1999, vol. 52, p. 1673-   [non-patent document 6] Annals of Neurology, 1998, vol. 43, p. 507-   [non-patent document 7] EXPERIMENTAL NEUROLOGY, 1999, vol. 162, p.    321

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide an agent for thetreatment and/or prophylaxis of a movement disorder such as a motorcontrol disorder (e.g., extrapyramidal syndrome or the like),hypermobility (e.g., dystonia, dyskinesia, tardive dyskinesia, tremor,chorea, ballism, akathisia, athetosis, bradykinesia, gait disturbance,freezing, rigidity, postural instability, myoclonus, tics or Tourettesyndrome, postural reflex disorder or the like), side effects of L-DOPAand/or dopamine agonist therapy (e.g., wearing-off phenomenon,dyskinesia or the like), or the like, an agent for the treatment and/orprophylaxis of Parkinson's disease and the like. Another object is toprovide a thiazole derivative or a pharmaceutically acceptable saltthereof having a selective adenosine A_(2A) antagonist, and useful asthe above-mentioned agent for the treatment and/or prevention, or apharmaceutically acceptable salt thereof.

Means of Solving the Problems

The present invention relates to the following (1)-(100).

(1) An agent for the treatment and/or prophylaxis of a movementdisorder, comprising a thiazole derivative represented by the formula(I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof as anactive ingredient.(2) The agent of (1), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(3) The agent of (1), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(4) The agent of any one of (1)-(3), wherein R² is pyridyl.(5) The agent of any one of (1)-(3), wherein R² is tetrahydropyranyl.(6) The agent of (1), wherein the thiazole derivative represented by theformula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(7) The agent of any one of (1)-(6), wherein the movement disorder is anextrapyramidal syndrome.(8) The agent of any one of (1)-(6), wherein the movement disorder isbradykinesia, gait disturbance, dystonia, dyskinesia or tardivedyskinesia.(9) The agent of any one of (1)-(6), wherein the movement disorder is aside effect of L-DOPA and/or dopamine agonist therapy.(10) The agent of (9), wherein the side effect is a motor complication.(11) The agent of (10), wherein the motor complication is wearing-offphenomenon.(12) The agent of (10), wherein the motor complication is on-offfluctuation.(13) The agent of (10), wherein the motor complication is dyskinesia.(14) The agent of any one of (1)-(13), wherein the movement disorder isthat developed in an advanced stage of Parkinson's disease.(15) A pharmaceutical composition comprising (a) a thiazole derivativerepresented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or adopamine agonist.(16) The pharmaceutical composition of (15), wherein R¹ is phenyl,pyridyl, pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from a fluorine atom, a chlorine atom, a bromineatom, methyl, ethyl, methoxy and ethoxy, and R² is pyridyl ortetrahydropyranyl.(17) The pharmaceutical composition of (15), wherein R¹ is pyridyl orpyrimidinyl, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl.(18) The pharmaceutical composition of any one of (15)-(17), wherein R²is pyridyl.(19) The pharmaceutical composition of any one of (15)-(17), wherein R²is tetrahydropyranyl.(20) The pharmaceutical composition of (15), wherein the thiazolederivative represented by the formula (I) is a compound represented byany one of the following formulas (IA)-(IAA).

(21) An agent for the treatment and/or prophylaxis of Parkinson'sdisease, comprising (a) a thiazole derivative represented by the formula(I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and(b) L-DOPA and/or a dopamine agonist in combination.(22) The agent of (21), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(23) The agent of (21), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(24) The agent of any one of (21)-(23), wherein R² is pyridyl.(25) The agent of any one of (21)-(23), wherein R² is tetrahydropyranyl.(26) The agent of (21), wherein the thiazole derivative represented bythe formula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(27) The agent of any one of (21)-(26), for administering (a) and (b)simultaneously or separately at an interval.(28) The agent of any one of (21)-(27), wherein the Parkinson's diseaseis that in an advanced stage.(29) A kit comprising (a) a first component comprising a thiazolederivative represented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, and (b) a secondcomponent comprising L-DOPA and/or a dopamine agonist.(30) The kit of (29), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(31) The kit of (29), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(32) The kit of any one of (29)-(31), wherein R² is pyridyl.(33) The kit of any one of (29)-(31), wherein R² is tetrahydropyranyl.(34) The kit of (29), wherein the thiazole derivative represented by theformula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(35) A method of treating and/or preventing a movement disorder,comprising administering an effective amount of a thiazole derivativerepresented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof.(36) The method of (35), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(37) The method of (35), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(38) The method of any one of (35)-(37), wherein R² is pyridyl.(39) The method of any one of (35)-(37), wherein R² istetrahydropyranyl.(40) The method of (35), wherein the thiazole derivative represented bythe formula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(41) The method of any one of (35)-(40), wherein the movement disorderis extrapyramidal syndrome.(42) The method of any one of (35)-(40), wherein the movement disorderis bradykinesia, gait disturbance, dystonia, dyskinesia or tardivedyskinesia.(43) The method of any one of (35)-(40), wherein the movement disorderis a side effect of L-DOPA and/or dopamine agonist therapy.(44) The method of (43), wherein the side effect is a motorcomplication.(45) The method of (44), wherein the motor complication is wearing-offphenomenon.(46) The method of (44), wherein the motor complication is on-offfluctuation.(47) The method of (44), wherein the motor complication is dyskinesia.(48) The method of any one of (35)-(47), wherein the movement disorderis that developed in an advanced stage of Parkinson's disease.(49) A method of treating and/or preventing. Parkinson's disease,comprising administering (a) an effective amount of a thiazolederivative represented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, and (b) an effectiveamount of L-DOPA and/or a dopamine agonist, simultaneously or separatelyat an interval.(50) The method of (49), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(51) The method of (49), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(52) The method of any one of (49)-(51), wherein R² is pyridyl.(53) The method of any one of (49)-(51), wherein R² istetrahydropyranyl.(54) The method of (49), wherein the thiazole derivative represented bythe formula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(55) The method of any one of (49)-(54), wherein the Parkinson's diseaseis that in an advanced stage.(56) A thiazole derivative represented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, foruse in the treatment and/or prophylaxis of a movement disorder.(57) The thiazole derivative or a pharmaceutically acceptable saltthereof of (56), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(58) The thiazole derivative or a pharmaceutically acceptable saltthereof of (56), wherein R¹ is pyridyl or pyrimidinyl, each of which isoptionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(59) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(58), wherein R² is pyridyl.(60) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(58), wherein R² is tetrahydropyranyl.(61) The thiazole derivative or a pharmaceutically acceptable saltthereof of (56), wherein the thiazole derivative represented by theformula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(62) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(61), wherein the movement disorder isextrapyramidal syndrome.(63) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(61), wherein the movement disorder isbradykinesia, gait disturbance, dystonia, dyskinesia or tardivedyskinesia.(64) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(61), wherein the movement disorder is a sideeffect of L-DOPA and/or dopamine agonist therapy.(65) The thiazole derivative or a pharmaceutically acceptable saltthereof of (64), wherein the side effect is a motor complication.(66) The thiazole derivative or a pharmaceutically acceptable saltthereof of (65), wherein the motor complication is wearing-offphenomenon.(67) The thiazole derivative or a pharmaceutically acceptable saltthereof of (65), wherein the motor complication is on-off fluctuation.(68) The thiazole derivative or a pharmaceutically acceptable saltthereof of (65), wherein the motor complication is dyskinesia.(69) The thiazole derivative or a pharmaceutically acceptable saltthereof of any one of (56)-(68), wherein the movement disorder is thatdeveloped in an advanced stage of Parkinson's disease.(70) A compound represented by any one of the following formulas(IE)-(IAA), or a pharmaceutically acceptable salt thereof.

(71) A combination of (a) a thiazole derivative represented by theformula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or adopamine agonist, for use in the treatment and/or prophylaxis ofParkinson's disease.(72) The combination of (71), wherein the use is for administering (a)and (b) simultaneously or separately at an interval.(73) The combination of (71) or (72), wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, and R² is pyridyl or tetrahydropyranyl.(74) The combination of (71) or (72), wherein R¹ is pyridyl orpyrimidinyl, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl.(75) The combination of any one of (71)-(74), wherein R² is pyridyl.(76) The combination of any one of (71)-(74), wherein R² istetrahydropyranyl.(77) The combination of (71) or (72), wherein the thiazole derivativerepresented by the formula (I) is a compound represented by any one ofthe following formulas (IA)-(IAA).

(78) The combination of any one of (71)-(77), wherein the Parkinson'sdisease is that in an advanced stage.(79) Use of a thiazole derivative represented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, for the manufacture of anagent for the treatment and/or prophylaxis of a movement disorder.(80) The use of (79), wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, and R² is pyridyl or tetrahydropyranyl.(81) The use of (79), wherein R¹ is pyridyl or pyrimidinyl, each ofwhich is optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen; lower alkyl optionally substituted by loweralkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(82) The use of any one of (79)-(81), wherein R² is pyridyl.(83) The use of any one of (79)-(81), wherein R² is tetrahydropyranyl.(84) The use of (79), wherein the thiazole derivative represented by theformula (I) is a compound represented by any one of the followingformulas (IA)-(IAA).

(85) The use of any one of (79)-(84), wherein the movement disorder isextrapyramidal syndrome.(86) The use of any one of (79)-(84), wherein the movement disorder isbradykinesia, gait disturbance, dystonia, dyskinesia or tardivedyskinesia.(87) The use of any one of (79)-(84), wherein the movement disorder is aside effect of L-DOPA and/or dopamine agonist therapy.(88) The use of (87), wherein the side effect is a motor complication.(89) The use of (88), wherein the motor complication is wearing-offphenomenon.(90) The use of (88), wherein the motor complication is on-offfluctuation.(91) The use of (88), wherein the motor complication is dyskinesia.(92) The use of any one of (79)-(91), wherein the movement disorder isthat developed in an advanced stage of Parkinson's disease.(93) Use of (a) a thiazole derivative represented by the formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl,or a pharmaceutically acceptable salt thereof, and (b) L-DOPA and/or adopamine agonist for the manufacture of an agent for the treatmentand/or prophylaxis of Parkinson's disease.(94) The use of (93), wherein the agent for the treatment and/orprophylaxis of Parkinson's disease is that for administering (a) and (b)simultaneously or separately at an interval.(95) The use of (93) or (94), wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, and R² is pyridyl or tetrahydropyranyl.(96) The agent of (93) or (94), wherein R¹ is pyridyl or pyrimidinyl,each of which is optionally substituted by 1 to 3 substituents selectedfrom the group consisting of halogen; lower alkyl optionally substitutedby lower alkoxy or morpholino; lower alkoxy; lower alkanoyl; and vinyl.(97) The use of any one of (93)-(96), wherein R² is pyridyl.(98) The use of any one of (93)-(96), wherein R² is tetrahydropyranyl.(99) The use of (93) or (94), wherein the thiazole derivativerepresented by the formula (I) is a compound represented by any one ofthe following formulas (IA)-(IAA).

(100) The use of any one of (93)-(99), wherein the Parkinson's diseaseis that in an advanced stage.

Effect of the Invention

The present invention provides an agent for the treatment and/orprophylaxis of a movement disorder, comprising a thiazole derivative ora pharmaceutically acceptable salt thereof as an active ingredient; apharmaceutical composition comprising (a) a thiazole derivative or apharmaceutically acceptable salt thereof and (b) L-DOPA and/or adopamine agonist; an agent for the treatment and/or prophylaxis ofParkinson's disease comprising (a) a thiazole derivative or apharmaceutically acceptable salt thereof and (b) L-DOPA and/or adopamine agonist in combination; a kit comprising (a) a first componentcomprising a thiazole derivative or a pharmaceutically acceptable saltthereof and (b) a second component comprising L-DOPA and/or a dopamineagonist; a thiazole derivative or a pharmaceutically acceptable saltthereof, which has a selective adenosine A_(2A) antagonistic activityand is useful for the treatment of a movement disorder, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of compound (IC) on the motor disability scorein the Test Example 3. The vertical axis shows the motor disabilityscore, and the horizontal axis shows time (min) after administration. ◯shows a combination of solvent and L-DOPA, and  shows a combination ofcompound (IC) and L-DOPA.

FIG. 2 shows the effect of compound (IC) on the maximum action (minimummotor disability score) in the Test Example 3. The vertical axis showsthe minimum motor disability score, and the horizontal axis shows theL-DOPA dasage. ◯ shows a combination of solvent and L-DOPA, and  showsa combination of compound (IC) and L-DOPA.

MODE FOR CARRYING OUT THE INVENTION

The movement disorder is a neurological condition characterized by motorcontrol disorder such as paucity or lack of movement, extrapyramidalsyndrome or the like, hypermobilities (e.g., dystonia, dyskinesia,tardive dyskinesia, tremor, chorea, ballism, akathisia, athetosis,bradykinesia, gait disturbance, freezing, rigidity, posturalinstability, myoclonus, tics or Tourette syndrome, postural reflexdisorder or the like) or the like.

The movement disorder in the agent for the treatment and/or prophylaxisof a movement disorder of the present invention means theabove-mentioned movement disorder, and preferably means, for example,motor control disorder such as extrapyramidal syndrome or the like,tremor, chorea, athetosis, bradykinesia, gait disturbance, dystonia,dyskinesia, tardive dyskinesia, postural reflex disorder or the like.Therefore, the agent for the treatment and/or prophylaxis of a movementdisorder of the present invention can treat and/or prevent or reduce orsuppress these diseases and/or symptoms (e.g., motor control disordersuch as extrapyramidal syndrome or the like, tremor, chorea, athetosis,bradykinesia, gait disturbance, dystonia, dyskinesia, tardivedyskinesia, postural reflex disorder or the like, preferably, forexample, extrapyramidal syndrome, bradykinesia, gait disturbance,dystonia, dyskinesia, tardive dyskinesia, postural reflex disorder orthe like, and more preferably, extrapyramidal syndrome, bradykinesia,gait disturbance, dystonia, dyskinesia, tardive dyskinesia or the like).

The movement disorder in the agent for the treatment and/or prophylaxisof a movement disorder of the present invention also encompasses sideeffects of L-DOPA and/or dopamine agonist therapy (e.g., motorcomplications such as wearing-off phenomenon, on-off fluctuation,dyskinesia or the like).

It is known that although L-DOPA provides robust and rapid therapeuticbenefits in Parkinson's disease, eventually, severe and uncomfortableadverse reactions including motor complications such as wearing-offphenomenon, on-off fluctuation, dyskinesia and the like appear (Marsdenet al., “Fluctuat ionsind is ability in Parkinson's disease: clinicalaspects” In: Marsden, C D, Fahn S., eds. Movement disorders. New York:Butterworth Scientific, p. 96-122 (1982)). It is also known that anadministration of L-DOPA alone causes side effects such as nausea,vomiting, anorexia and the like.

A dopamine agonist can also induce dyskinesia. Use of a dopamine agonistis often limited due to neuropsychiatric side effects, particularly,hallucination and psychosis. Although a dopamine agonist providesadvantages when used as the adjunct in the treatment with L-DOPA,control thereby of motor complication caused by L-DOPA is extremelydifficult or even impossible, as mentioned above (Olanow, Watts andKollereds., An Algorithm (Decision Tree) for the Management ofParkinson's Disease: Treatment Guidelines, Neurology 56, Suppl. 5(2001)). Furthermore, it is reported that excessive daytime sleepinessassociated with Parkinson's disease may be aggravated by L-DOPA and/or adopamine agonist (Neurology, vol. 67, p. 853 (2006)).

The side effects in the L-DOPA and/or dopamine agonist therapy in thepresent invention refer to the above-mentioned side effects that occurin the treatment and/or prophylaxis of Parkinson's disease and the likeusing L-DOPA and/or a dopamine agonist. For example, they include motorcomplications such as wearing-off phenomenon, on-off fluctuation,dyskinesia and the like, nausea, vomiting, anorexia, hallucination andpsychological symptom, excessive daytime sleepiness, preferably, motorcomplications such as wearing-off phenomenon, on-off fluctuation,dyskinesia and the like, and the like. That is, the agent for thetreatment and/or prophylaxis of a movement disorder of the presentinvention can reduce or suppress a side effect that appears onadministration of L-DOPA and/or a dopamine agonist, specifically, amotor complication such as wearing-off phenomenon, on-off fluctuation,dyskinesia or the like, nausea, vomiting, anorexia, hallucination andpsychological symptom, or excessive daytime sleepiness, preferably, amotor complication such as wearing-off phenomenon, on-off fluctuation,dyskinesia or the like, more preferably, a symptom such as wearing-offphenomenon, dyskinesia or the like.

As Parkinson's disease progresses, more dopamine cells die and theremaining cells cannot store sufficient dopamine to maintain itsbenefits in the L-DOPA and/or dopamine agonist therapy. As a result, theduration of action at each dose decreases and patients need higher ormore frequent doses. After 2-5 years, as many as 50-75% of the patientsexperience fluctuations in their response to L-DOPA, for example, inlength of on-time and the like. Along with the fluctuations, thepatients develop wearing-off phenomenon, on-off fluctuation, dyskinesia(involuntary movement) or the like which accompany the fluctuations inthe duration of action. Thus, continuation of the L-DOPA and/or dopamineagonist therapy may be difficult due to the onset of such side effectsand the like. Therefore, the agent for the treatment and/or prophylaxisof a movement disorder of the present invention can extend the effectivetime of the treatment with L-DOPA and/or a dopamine agonist by reducingor suppressing the above-mentioned side effects. Particularly, the agentfor the treatment and/or prophylaxis of a movement disorder of thepresent invention can effectively suppress the wearing-off phenomenon orthe like, which are problematic in L-DOPA therapy of patients withParkinson's disease in an advanced stage.

L-DOPA used for the above-mentioned L-DOPA and/or dopamine agonisttherapy may contain L-DOPA or a salt, hydrate, prodrug or the likethereof as an active ingredient, and examples thereof includepreparations containing these as an active ingredient and the like.Examples of the commercially available product include Menesit(registered trade mark), EC Doparl (registered trade mark), Doparl(registered trade mark), Madopar (registered trade mark) and the like.The dopamine agonist may contain a dopamine agonist or a salt, hydrate,prodrug or the like thereof as an active ingredient, and examplesthereof include preparations containing pramipexole, talipexole,ropinirole, cabergoline, pergolide or the like, or a hydrochloride,mesylate or prodrug thereof or the like as an active ingredient, and thelike. Examples of the commercially available product include Domin(registered trade mark), Permax (registered trade mark), Cabaser(registered trade mark) and the like.

The agent for the treatment and/or prophylaxis of Parkinson's disease ofthe present invention characteristically comprises a thiazole derivativeor a pharmaceutically acceptable salt thereof and L-DOPA and/or adopamine agonist in combination, and not only can reduce or suppresseach symptom of Parkinson's disease, but also can delay the onset of theside effect caused by the administration of the aforementioned L-DOPAand/or a dopamine agonist (e.g., wearing-off phenomenon, on-offfluctuation, dyskinesia or the like) or suppress the symptoms.

In the following, the compound represented by the formula (I) isreferred to as Compound (I). The compounds having other formula numbersare also referred to in the same manner.

The definition of each group in the formula (I) is as follows.

Examples of the lower alkyl moiety of the lower alkyl, the lower alkoxyand the lower alkanoyl include straight or branched alkyl having 1 to 10carbon atoms, and more specific examples thereof include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.

Examples of the aralkyl include aralkyl having 7 to 16 carbon atoms, andmore specific examples thereof include benzyl, phenethyl, phenylpropyl,phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl,phenylnonyl, phenyldecyl, naphthylmethyl, naphthylethyl, naphthylpropyl,naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl,anthrylethyl and the like.

Examples of the aryl include aryl having 6 to 14 carbon atoms, and morespecific examples thereof include phenyl, naphthyl, azulenyl, anthryland the like.

Examples of the aromatic heterocyclic group include a 5-membered or6-membered monocyclic aromatic heterocyclic group containing at leastone atom selected from a nitrogen atom, an oxygen atom and a sulfuratom, a bicyclic or tricyclic fused aromatic heterocyclic group in which3 to 8-membered rings are fused, having at least one atom selected froma nitrogen atom, an oxygen atom, and a sulfur atom, and the like. Morespecific examples thereof include furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl,benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, furo[2,3-b]pyridyl,6,7-dihydro-5H-cyclopenta[b]pyridyl,7,8-dihydro-5H-pyrano[4,3-b]pyridyl,7,8-dihydro-5H-thiopyrano[4,3-b]pyridyl and the like.

Examples of the aromatic heterocycle-alkyl include a group wherein anaromatic heterocyclic group is bonded to alkylene. The aromaticheterocyclic group include those exemplified in the above-mentionedaromatic heterocyclic group, and the alkylene include an alkylene having1 to 10 carbon atoms, and specific examples thereof include methylene,ethylene, trimethylene, propylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene,decamethylene and the like. Specific examples of the aromaticheterocycle-alkyl include pyrrolylmethyl, pyrrolylethyl,thiazolylmethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl,pyrimidinylethyl, indolylmethyl, benzimidazolylmethyl and the like.

Examples of the aliphatic heterocycle-alkyl include a group wherein thealiphatic heterocyclic group is bonded to alkylene. Examples of thealiphatic heterocyclic group include a 5-membered or 6-memberedmonocyclic aliphatic heterocyclic group containing at least one atomselected from a nitrogen atom, an oxygen atom and a sulfur atom, abicyclic or tricyclic fused aliphatic heterocyclic group in which 3 to8-membered rings are fused, having at least one atom selected from anitrogen atom, an oxygen atom, and a sulfur atom, and the like. Morespecific examples thereof include aziridinyl, azetidinyl, pyrrolidinyl,piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl,imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl,pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,5,6-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyridyl, oxazolidinyl,morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl,2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl,benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl,benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl,dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl,tetrahydroquinazolinyl, dihydrobenzodioxanyl and the like. Examples ofthe alkylene include alkylene having 1 to 10 carbon atoms, and specificexamples thereof include methylene, ethylene, trimethylene, propylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,octamethylene, nonamethylene, decamethylene and the like. Specificexamples of the aliphatic heterocycle-alkyl include5,6-dihydro-2H-pyridylmethyl, 5,6-dihydro-2H-pyridylethyl,tetrahydro-2H-pyranylmethyl, 5,6-dihydro-2H-pyranylmethyl,5,6-dihydro-2H-pyranylethyl, morpholinomethyl, morpholinoethyl,piperazinylmethyl, oxazolidinylmethyl and the like.

The halogen means each atom of fluorine, chlorine, bromine and iodine.

Compound (I) or a pharmaceutically acceptable salt thereof of thepresent invention or used in the present invention is preferably acompound having a potent antagonistic activity against adenosine A_(2A)receptors from among various subtypes of adenosine receptors (e.g.,adenosine A₁, A_(2A), A_(2B) and A₃ receptors).

Accordingly, Compound (I) or a pharmaceutically acceptable salt thereofof the present invention or used in the present invention is preferablya compound having a strong affinity for the adenosine A_(2A) receptors.For example, the compound is preferably one having an inhibitoryactivity of 50% or more at a test compound concentration of 3×10⁻⁸mol/L, more preferably one having an inhibitory activity of 50% or moreat a test compound concentration of 1×10⁻⁸ mol/L, still more preferablyone having an inhibitory activity of 50% or more at a test compoundconcentration of 3×10⁻⁹ mol/L, further preferably one having aninhibitory activity of 50% or more at a test compound concentration of1×10⁻⁹ mol/L, in the adenosine A_(2A) receptor binding test shown in thebelow-mentioned Test Example 1. In addition, the compound is preferablyone having an inhibitory activity of 30 nmol/L or less in an inhibitoryconstant (Ki value), more preferably one having an inhibitory activityof 10 nmol/L or less, still more preferably one having an inhibitoryactivity of 3 nmol/L or less, further preferably one having aninhibitory activity of 1 nmol/L or less.

Further, Compound (I) or a pharmaceutically acceptable salt thereof ofthe present invention or used in the present invention is preferably acompound having selective affinity for the adenosine A_(2A) receptorsfrom among various subtypes of the adenosine receptors. For example, acompound having a higher affinity for the adenosine A_(2A) receptorsthan that for the adenosine A₁ receptors is preferable. Specifically,for example, the compound is preferably a compound having 5 times ormore affinity, more preferably 10 times or more affinity, furtherpreferably 50 times or more affinity, even more preferably 100 times ormore affinity, most preferably 500 times or more affinity for theadenosine A_(2A) receptors than that for the adenosine A₁ receptors.

The affinity for adenosine receptors can be determined according to aconventional method, for example, according to the method of TestExample 1 to be mentioned below, or the methods described in, forexample, a document [for example, Naunyn Schmiedebergs Arch Pharmacol.,355(1), p. 59 (1987); Naunyn Schmiedebergs Arch Pharmacol. 355(2), p.204 (1987); Br. J. Pharmacol. 117(8), p. 1645 (1996) and the like].

More specifically, Compound (I) is preferably a compound wherein R¹ isphenyl optionally substituted by 1 to 3 substituents selected fromhalogen, C₁₋₆ alkyl optionally substituted by C₁₋₆ alkoxy or morpholino,C₁₋₆ alkanoyl, vinyl and C₁₋₆ alkoxy; pyridyl optionally substituted by1 to 3 substituents selected from halogen, C₁₋₆ alkyl optionallysubstituted by C₁₋₆ alkoxy or morpholino, C₁₋₆ alkanoyl, vinyl and C₁₋₆alkoxy; pyrimidinyl optionally substituted by 1 to 3 substituentsselected from halogen, C₁₋₆ alkyl optionally substituted by C₁₋₆ alkoxyor morpholino, C₁₋₆ alkanoyl, vinyl and C₁₋₆ alkoxy;5,6-dihydro-2H-pyridylmethyl optionally substituted by 1 to 3substituents selected from halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy;2,3,4,5-tetrahydropyranyloxy; pyrrolyl; indolyl; oxazolopyridyl;quinolyl; 1H-3,4-dihydropyranopyridinyl;1H-3,4-dihydrothiopyranopyridinyl; cyclopentapyridyl; or pyridylmethyl,

more preferably a compound wherein R¹ is phenyl optionally substitutedby 1 to 3 substituents selected from a fluorine atom, a chlorine atom,methyl and methoxy; pyridyl optionally substituted by 1 to 3substituents selected from a fluorine atom, a chlorine atom, methyl andmethoxy; pyrimidinyl optionally substituted by 1 to 3 substituentsselected from a fluorine atom, a chlorine atom, methyl and methoxy;5,6-dihydro-2H-pyridylmethyl optionally substituted by 1 to 3substituents selected from a fluorine atom, a chlorine atom, methyl andmethoxy; or 2,3,4,5-tetrahydropyranyloxy, still more preferably acompound wherein R¹ is pyridyl substituted by 1 to 3 substituentsselected from a chlorine atom, methyl and methoxy; pyrimidinylsubstituted by 1 to 3 substituents selected from chlorine atom, methyland methoxy; 5,6-dihydro-2H-pyridylmethyl; or2,3,4,5-tetrahydropyranyloxy. More specifically, Compound (I) ispreferably, for example, compounds of the following formulas (IA)-(IAA),and the like.

The pharmaceutically acceptable salts of Compound (I) include, forexample, pharmaceutically acceptable acid addition salts, metal salts,ammonium salts, organic amine addition salts, amino acid addition salts,and the like. The pharmaceutically acceptable acid addition salts ofCompound (I) include, for example, inorganic acid salts such ashydrochloride, hydrobromate, nitrate, sulfate, and phosphate; organicacid salts such as acetate, oxalate, maleate, fumarate, citrate,benzoate, and methane sulfonate, and the like. Examples of thepharmaceutically acceptable metal salts include alkali metal salts suchas a sodium salt, and a potassium salt; alkaline earth metal salts suchas a magnesium salt, and a calcium salt; an aluminum salt; a zinc salt,and the like. Examples of the pharmaceutically acceptable ammonium saltsinclude salts of ammonium, tetramethylammonium, and the like. Examplesof the pharmaceutically acceptable organic amine addition salts includeaddition salts of morpholine, piperidine, or the like. Examples of thepharmaceutically acceptable amino acid addition salts include additionsalts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid,or the like.

Compound (I) can be produced according to a known method, for example,the method described in WO 2005/063743 and the like.

wherein R¹ and R² are as defined above, and X is a chlorine atom, abromine atom or the like.

Specifically, as shown in the above-mentioned formula, Compound (I) canbe produced, for example, by reacting compound (Ia) described in WO2005/063743 with preferably 0.5 to 5 equivalents of compound (Ib) in asolvent such as methanol, dichloromethane, chloroform, toluene, ethylacetate, acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), pyridine, water, or a mixed solventthereof and the like, preferably in the presence of 1 to 5 equivalentsof a condensing agent such as 1,3-dicyclohexanecarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride andthe like, if necessary, in the presence of preferably 1 to 5 equivalentsof 1-hydroxybenzotriazole (HOBt) monohydrate, 4-dimethylaminopyridine(DMAP) and the like, at a temperature between −20° C. and the boilingpoint of the solvent used, for 5 min to 72 hr.

Alternatively, Compound (I) can also be produced, for example, byreacting compound (Ia) described in WO 2005/063743 with preferably 1 to10 equivalents of compound (Ic) without solvent or in a solvent such asdichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate,acetonitrile, THF, DMF, DMA, pyridine and the like, if necessary, in thepresence of preferably 1 to 10 equivalents of a base such as potassiumcarbonate, triethylamine, 4-dimethylaminopyridine (DMAP) and the like,at a temperature between −20° C. and 150° C., for 5 min to 72 hr.

Compound (I) may exist as stereoisomers such as geometrical isomers oroptical isomers, or tautomers. The thiazole derivative or apharmaceutically acceptable salt thereof of the present inventionencompasses all possible isomers including those and mixtures thereof.All possible isomers including those and mixtures thereof can be usedfor an agent for the treatment and/or prophylaxis of a movementdisorder, a pharmaceutical composition, an agent for the treatmentand/or prophylaxis of Parkinson's disease, a kit, a method for thetreatment and/or prophylaxis of a movement disorder, a method for thetreatment and/or prophylaxis of Parkinson's disease, a combination, usefor the manufacture of an agent for the treatment and/or prophylaxis ofa movement disorder and use for the manufacture of an agent for thetreatment and/or prophylaxis of Parkinson's disease, of the presentinvention.

To obtain a salt of Compound (I), when the Compound (I) is obtained inthe form of a salt, it may be purified as it is. Further, when thecompound is obtained in a free form, the compound may be dissolved orsuspended in a suitable solvent, followed by addition of an acid or abase to form a salt. Then, the resulting salt may be isolated andpurified.

The Compound (I) or a pharmaceutically acceptable salt thereof may existin the form of an adduct with water or various solvents. Such adduct isalso encompassed in the thiazole derivative or a pharmaceuticallyacceptable salt thereof of the present invention, and can be used for anagent for the treatment and/or prophylaxis of a movement disorder, apharmaceutical composition, an agent for the treatment and/orprophylaxis of Parkinson's disease, a kit, a method for the treatmentand/or prophylaxis of a movement disorder, a method for the treatmentand/or prophylaxis of Parkinson's disease, a combination, use for themanufacture of an agent for the treatment and/or prophylaxis of amovement disorder and use for the manufacture of an agent for thetreatment and/or prophylaxis of Parkinson's disease, of the presentinvention.

L-DOPA used for a pharmaceutical composition, an agent for the treatmentand/or prophylaxis of Parkinson's disease, a kit, a method for thetreatment and/or prophylaxis of Parkinson's disease, a combination anduse for the manufacture of an agent for the treatment and/or prophylaxisof Parkinson's disease, of the present invention may contain, as anactive ingredient, L-DOPA or a salt, hydrate, prodrug or the likethereof and, for example, a preparation and the like containing these asactive ingredients can be used. Such L-DOPA can be obtained, forexample, as a commercially available product, or can be produced by aknown method. Specific examples of the commercially available productinclude Menesit (registered trade mark), EC Doparl (registered trademark), Doparl (registered trade mark), Madopar (registered trade mark)and the like.

The dopamine agonist used for a pharmaceutical composition, an agent forthe treatment and/or prophylaxis of Parkinson's disease, a kit, a methodfor the treatment and/or prophylaxis of Parkinson's disease, acombination and use for the manufacture of an agent for the treatmentand/or prophylaxis of Parkinson's disease, of the present invention maycontain, as an active ingredient, a dopamine agonist or a salt, hydrate,prodrug or the like thereof and, for example, a preparation and the likecontaining these as active ingredients can be used. Specific examplesthereof include pramipexole, talipexole, ropinirole, cabergoline,pergolide and the like, or a hydrochloride, mesylate, prodrug thereofand the like, and a preparation and the like containing these as activeingredients can also be used. Such dopamine agonist can be obtained, forexample, as a commercially available product, or can be produced by aknown method. Specific examples of the commercially available productinclude Domin (registered trade mark), Permax (registered trade mark),Cabaser (registered trade mark) and the like.

The pharmaceutical preparation according to an agent for the treatmentand/or prophylaxis of a movement disorder, a method for the treatmentand/or prophylaxis of a movement disorder and use for the manufacture ofan agent for the treatment and/or prophylaxis of a movement disorder, ofthe present invention may contain, as the active ingredient, Compound(I) or a pharmaceutically acceptable salt thereof either alone or as amixture with any other therapeutic active ingredient. Furthermore, thesepharmaceutical preparations are prepared by mixing the active ingredientwith one or more pharmaceutically acceptable carriers (for example,diluents, solvents, excipients, or the like), and then subjecting themixture to any method well-known in the technical field ofpharmaceutics.

As for the administration route, it is preferable to select the mosteffective route of administration for treatment. Examples of theadministration route include oral administration, and parenteraladministration, for example, such as intravenous or transdermaladministration and the like.

Examples of the dosage form include tablets, injections, externalpreparations, and the like.

Suitable dosage forms for the oral administration, for example, tablets,can be prepared by using excipients such as lactose, disintegrators suchas starch, lubricants such as magnesium stearate, or binders such ashydroxypropylcellulose, or the like.

Suitable dosage forms for the parenteral administration, for example,injections, can be prepared by using diluents or solvents such as asaline solution, a glucose solution, or a mixture of brine and glucosesolution, or the like. A dosage form suitable for external preparationis not particularly limited and, for example, ointment, cream, liniment,lotion, cataplasm, plaster, tape and the like can be included. Forexample, ointment, cream and the like can be produced by, for example,dissolving or mixing-dispersing the active ingredient in a base such aswhite petrolatum and the like.

The dose and administration frequency of Compound (I) or apharmaceutically acceptable salt thereof varies depending on theefficacy, dose and/or administration form, age and body weight ofpatients, properties or severity of the symptoms to be treated and thelike. For general oral administration, 0.001-1000 mg, preferably0.05-100 mg, is administered to one adult in one to several portions aday. For parenteral administration such as intravenous administrationand the like, 0.001-1000 mg, preferably 0.01-100 mg, is generallyadministered to one adult in one to several portions a day. Fortransdermal administration, an external preparation containing 0.001-10%of Compound (I) or a pharmaceutically acceptable salt thereof isgenerally applied once to several times a day. However, these doses andadministration frequencies vary depending on the aforementioned variousconditions.

The agent for the treatment and/or prophylaxis of a movement disorder,the method of treating and/or preventing a movement disorder and thethiazole derivative or a pharmaceutically acceptable salt thereof foruse in the treatment and/or prophylaxis of a movement disorder of thepresent invention shows a superior therapeutic and/or prophylactic, orreducing and/or suppressive effect on a movement disorder such asextrapyramidal syndrome, bradykinesia, gait disturbance, dystonia,dyskinesia, tardive dyskinesia or the like; and a side effect of L-DOPAand/or dopamine agonist therapy such as wearing-off phenomenon, on-offfluctuation, dyskinesia or the like. Particularly, it shows a superiortherapeutic and/or prophylactic, or reducing and/or suppressive effecton the above-mentioned disease developed in Parkinson's disease in anadvanced stage (e.g., a movement disorder such as extrapyramidalsyndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardivedyskinesia or the like; and a side effect of L-DOPA and/or dopamineagonist therapy such as wearing-off phenomenon, on-off fluctuation,dyskinesia or the like).

As mentioned above, Compound (I) or a pharmaceutically acceptable saltthereof may be used in combination with one or more other pharmaceuticalcomponents.

Examples of the other pharmaceutical components used in combinationinclude known drugs useful as therapeutic and/or prophylactic drug forParkinson's disease and the like, and the like, and the like (Iyaku(Medicine and Drug) Journal, vol. 44, p. 91 (2008)). Specifically, forexample, COMT inhibitors (e.g., entacapone, tolcapone and the like), MAOinhibitors (e.g., selegiline, rasagiline and the like) and the like canbe included.

When Compound (I) or a pharmaceutically acceptable salt thereof is usedin combination with other pharmaceutical component(s), Compound (I) or apharmaceutically acceptable salt thereof, and other pharmaceuticalcomponent(s) may be administered simultaneously or separately at aninterval. The doses vary depending on the administration subject, theadministration route, the disease, and the combinations ofpharmaceutical component, and the like, and should be decided accordingto the doses used in the clinic.

(a) Compound (I) or a pharmaceutically acceptable salt thereof and (b)L-DOPA and/or a dopamine agonist used for the pharmaceuticalcomposition, the agent for the treatment and/or prophylaxis ofParkinson's disease, the kit, the method for the treatment and/orprophylaxis of Parkinson's disease, the combination and the use for themanufacture of an agent for the treatment and/or prophylaxis ofParkinson's disease, of the present invention may be used oradministered as a single preparation (combination agent) or as acombination of more than one preparation, provided that thesepreparations are formulated together with, for example, apharmaceutically acceptable carrier to contain these active ingredients.In particular, a combination of two or more preparations is preferred.When used or administered as a combination of more than one preparation,the preparations may be used or administered simultaneously orseparately at an interval. Preferably, these preparations are used inthe form of, for example, tablets, injections, external preparations orthe like.

The dose ratio (weight/weight) of (a) Compound (I) or a pharmaceuticallyacceptable salt thereof and (b) L-DOPA and/or a dopamine agonist can beappropriately adjusted according to a combination of (a) Compound (I) ora pharmaceutically acceptable salt thereof and (b) L-DOPA and/or adopamine agonist used, efficacy of each of (a) Compound (I) or apharmaceutically acceptable salt thereof and (b) L-DOPA and/or adopamine agonist and the like. Specifically for example, it is 1/100000((a) Compound (I) or a pharmaceutically acceptable salt thereof/(b)L-DOPA and/or a dopamine agonist)-1000/1, preferably 1/50000-500/1, morepreferably 1/6000-100/1, further more preferably 1/4000-15/1, stillfurther more preferably 1/1000-10/1, most preferably 1/100-10/1.

These preparations are prepared by mixing the active ingredient with oneor more pharmaceutically acceptable carriers (for example, diluents,solvents, excipients, or the like), and then subjecting the mixture toany method well known in the technical field of pharmaceutics.

Suitable dosage forms for the oral administration, for example, tablets,can be prepared by using excipients such as lactose, disintegrators suchas starch, lubricants such as magnesium stearate, binders such ashydroxypropylcellulose, or the like.

Suitable dosage forms for the parenteral administration, for example,injections, can be prepared by using diluents or solvents such as asaline solution, a glucose solution, or a mixture of brine and glucosesolution, or the like. A dosage form suitable for external preparationis not particularly limited to and, for example, ointment, cream,liniment, lotion, cataplasm, plaster, tape and the like can be included.For example, ointment, cream and the like can be produced by, forexample, dissolving or mixing-dispersing the active ingredient in a basesuch as white petrolatum and the like.

When administered as a combination of more than one preparation, forexample, (a) a first component comprising Compound (I) or apharmaceutically acceptable salt thereof, and (b) a second componentcomprising L-DOPA and/or a dopamine agonist may be separately preparedinto a kit, and may be administered to the same subject in the sameroute or in different routes simultaneously or separately at aninterval, using the kit.

As the kit, for example, a kit comprising contents and two or morecontainers (for example, vials, bags, etc.) whose material, shape, andso on are not particularly limited as long as the containers do notcause degeneration of the components which are the contents due toexternal temperature or light nor cause elution of chemical componentsfrom the containers during storage, and having a form which enables theadministration of the above first and second components which are thecontents through separate routes (for example, tubes, etc.) or the sameroute is used. Specific examples thereof include tablet kits, injectionkits, and the like.

When (a) Compound (I) or a pharmaceutically acceptable salt thereof and(b) L-DOPA and/or a dopamine agonist are used or administered as acombination of plural preparations for the above-mentioned objects, thedose and administration frequency vary depending on the efficacy of eachactive ingredient, dosage form, age and body weight of a patient,symptom, and the like. It is preferable to administer each of (a)Compound (I) or a pharmaceutically acceptable salt thereof and (b)L-DOPA and/or a dopamine agonist usually at the following dose per day.

For oral administration as, for example, tablet, (a) Compound (I) or apharmaceutically acceptable salt thereof and (b) L-DOPA and/or adopamine agonist are administered at 0.1-1000 mg and 0.1-10000 mg,preferably 0.1-500 mg and 0.1-5000 mg, more preferably 0.5-500 mg and1-3000 mg, still more preferably 0.5-300 mg and 1-2000 mg, respectively,per one adult simultaneously or separately at an interval in one toseveral portions a day usually.

For parenteral administration as, for example, injection and the like,(a) Compound (I) or a pharmaceutically acceptable salt thereof and (b)L-DOPA and/or a dopamine agonist are administered at 0.1-1000 mg and0.1-10000 mg, preferably 0.1-500 mg and 0.1-5000 mg, more preferably0.5-500 mg and 1-3000 mg, still more preferably 0.5-300 mg and 1-2000mg, respectively, per one adult simultaneously or separately at aninterval in one to several portions a day usually.

When (a) Compound (I) or a pharmaceutically acceptable salt thereof and(b) L-DOPA and/or a dopamine agonist are used or administered as asingle preparation for the above-mentioned objects, the dose andadministration frequency vary depending on the efficacy of each activeingredient, dosage form, age and body weight of a patient, symptom, andthe like. It is preferable to prepare one preparation containing eachdose in the use or administration of a combination of theabove-mentioned plural preparations, and use or administer same.

However, such dose and administration frequency vary depending on theaforementioned various conditions.

A pharmaceutical composition, an agent for the treatment and/orprophylaxis of Parkinson's disease, a kit, a method for the treatmentand/or prophylaxis of Parkinson's disease, and a combination of thepresent invention can be used for, for example, the treatment and/orprophylaxis of Parkinson's disease, more specifically, for patients, forexample, patients with Parkinson's disease in an advanced stage,patients with Parkinson's disease who developed symptoms of on-offfluctuation, wearing-off phenomenon, dyskinesia or the like due toL-DOPA therapy or the like, and the like, and can effectively treatthese diseases.

Next, the therapeutic effect of Compound (I) or a pharmaceuticallyacceptable salt thereof on movement disorders, the effect of combinedadministration of (a) Compound (I) or a pharmaceutically acceptable saltthereof and (b) L-DOPA and/or a dopamine agonist and the like arespecifically explained in the following Test Examples.

Test Example 1 Adenosine Receptor Binding Action (1) Adenosine A_(2A)Receptor Binding Test

The test can be performed according to, for example, the method ofVarani et al. (British Journal of Pharmacology, 1996, 117, p. 1693).

Specifically, for example, human recombinant receptors are expressed inHEK-293 cells. The cell membranes of the receptor-expressing cells arecollected, and a cell membrane suspension is prepared. After dilutionwith tris(hydroxymethyl)-aminomethane hydrochloride (Tris HCl) buffer,tritium-labeled CGS-21680(³H-2-[p-(2-carboxyethyl)phenethylamino]-5′-(N-ethylcarboxamido)adenosine:50 mmol/L) and a test compound solution (dimethyl sulfoxide solution ofthe test compound) are added to the cell membrane suspension for bindingto the receptors. After the reaction, the mixture is subjected to rapidsuction filtration using glass-fiber filter paper, and the radioactivityof the glass-fiber filter paper is measured. In this way, the inhibitoryrate of the test compound for the human adenosine A_(2A) receptorbinding (³H-CGS21680 binding) can be determined.

The test can also be performed according to the method of Bruns et al.(Molecular Pharmacology, Vol. 29, p. 331, 1986).

Specifically, for example, rat striatum is suspended in 50 ml ofice-cooled Tris HCl buffer (50 mmol/L, pH 7.7) using a Polytronhomogenizer and the suspension is centrifuged. The resulting precipitateis resuspended by adding Tris HCl buffer (50 mmol/L) thereto, followedby centrifugation in the same manner. The resulting final precipitate issuspended in Tris HCl buffer (50 mmol/L) [containing magnesium chloride(10 mmol/L), and adenosine deaminase (0.02 units/mg tissue)] to preparethe suspension at the tissue concentration of 5 mg (wet weight)/mL.Tritium-labeled CGS-21680 (final concentration of 6.0 mmol/L), and thetest compound solution (dimethylsulfoxide solution of test compounddiluted with Tris HCl buffer) are added. The mixture is allowed to standat 25° C. for 120 minutes, followed by rapid suction filtration usingglass-fiber filter paper, and then immediately washed with ice-cooledTris HCl buffer (50 mmol/L). The glass-fiber filter paper is then placedin a vial, and MicroScinti (PKI) is added. Then, the radioactivity ismeasured with a TopCount (PerkinElmer), whereby the inhibitory rate forrat adenosine A_(2A) receptor binding (³H-CGS21680 binding) of the testcompound can be determined.

The inhibitory rate can be calculated by the following equation.

${{Inhibitory}\mspace{14mu} {rate}\; (\%)} = {\left( {1 - \frac{\begin{matrix}{{{Amount}\mspace{14mu} {of}\mspace{14mu} {binding}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {presence}\mspace{14mu} {of}\mspace{14mu} {drug}} -} \\{{amount}\mspace{14mu} {of}\mspace{14mu} {non}\text{-}{specific}\mspace{14mu} {binding}}\end{matrix}}{\begin{matrix}{{{Total}\mspace{14mu} {amount}{\mspace{11mu} \;}{of}\mspace{14mu} {binding}} -} \\{{amount}\mspace{14mu} {of}\mspace{14mu} {non}\text{-}{specific}\mspace{14mu} {binding}}\end{matrix}}} \right) \times 100}$

In the equation, the total amount of binding refers to the boundradioactivity of ³H-CGS21680 in the absence of the test compound. Theamount of non-specific binding refers to the bound radioactivity of³H-CGS21680 in the presence of 50 μmol/L of5′-N-ethylcarboxamideadenosine (NECA) or 100 μmol/L ofcyclopentyladenosine (CPA). The amount of binding in the presence ofdrug refers to the bound radioactivity of ³H-CGS21680 in the presence ofthe test compound.

In the above test, the inhibitory rate for the adenosine A_(2A) receptorat different concentrations of the test compound or a pharmaceuticallyacceptable salt thereof, and the test compound concentration at whichthe test compound inhibits binding by 50% (IC₅₀) can be calculated byappropriately adjusting the concentration of the test compound.

The inhibition constant (Ki value) of the test compound for theadenosine A_(2A) receptor binding can be calculated according to thefollowing equation.

Ki=IC ₅₀/(1+L/Kd)

In the equation, L denotes the concentration of the ³H-CGS21680 used inthe test, and Kd is the dissociation constant of the ³H-CGS21680 used inthe test.

Instead of ³H-CGS21680, ³H-SCH58261(³H-5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)and the like may be used.

(2) Adenosine A₁ Receptor Binding Test

The inhibition constant (Ki value) of the test compound for theadenosine A₁ receptor can be calculated in the same manner as in (1),using the materials below.

Specifically, for example, human A₁ receptor-expressing CHO cellmembranes are used, and, as the labeled compound, for example,tritium-labeled DPCPX (1,3-dipropyl-8-cyclopentylxanthine) is used. Theamount of non-specific binding can be determined by measuring the³H-DPCPX bound radioactivity in the presence of, for example, 100 μmol/Lof R(−)-PIA((−)-N⁶-2-phenylisopropyl adenosine). The affinity of thetest compound for the human adenosine A₁ receptors can be confirmed inthis manner.

Alternatively, for example, rat A₁ receptor-expressing cell membrane(PerkinElmer) is used, and as the labeled compound, for example,tritium-labeled CHA (N⁶-cyclohexyladenosine) is used. For themeasurement of the amount of non-specific binding, ³H-CHA boundradioactivity is measured in the presence of, for example, 10 μmol/L ofDPCPX, and the affinity of the test compound for the rat adenosine A₁receptor can be confirmed.

By the foregoing tests (1) and (2), the selective affinities of thethiazole derivative or a pharmaceutically acceptable salt thereof usedin the present invention for the adenosine A_(2A) receptor can beconfirmed.

(3) Affinity of Compound (I) or a Pharmaceutically Acceptable SaltThereof for Adenosine Receptors

Some of the examples of the affinities of Compound (I) or apharmaceutically acceptable salt thereof for the adenosine A₁ receptorand the adenosine A_(2A) receptor are presented below. Note that thetest results below are those measured by MDS Pharma Services Inc.according to the foregoing methods.

TABLE 1 The affinities for adenosine receptors Inhibitory rate forInhibitory rate for human adenosine A_(2A) human adenosine A₁ compoundreceptor binding (³H- receptor binding (³H- No. CGS21680 binding)* DPCPXbinding)* (IA) 92% 14% (IB) 98%  4% (IC) 88% 29% (ID) 100%  28%*Inhibitory rate at compound of 100 nmol/L

Test Example 2 Adenosine Receptor Binding Activity (2)

In the same manner as in the above-mentioned Test Example 1, theaffinity of compound (IE)-(IAA) for adenosine receptor was confirmed(test results were those measured by Ricerca Biosciences, LLC accordingto the foregoing methods).

TABLE 2 The affinities for adenosine receptors Inhibitory rate forInhibitory rate for Inhibitory rate for Inhibitory rate for humanadenosine human adenosine human adenosine human adenosine A_(2A)receptor binding A₁ receptor A_(2A) receptor binding A₁ receptorcompound (³H-CGS21680 binding (³H-DPCPX compound (³H-CGS21680 binding(³H-DPCPX No. binding)* binding)* No. binding)* binding)* (IE) 93% 33%(IF) 107%  50% (IG) 102%  91% (IH) 98% 67% (II) 85% 19% (IJ) 93% 21%(IK) 92% 24% (IL) 85% 20% (IM) 98% 47% (IN) 93% 21% (IO) 97% 56% (IP)98% 18% (IQ) 100%  18% (IR) 107%  30% (IS) 90% 10% (IT) 91% 37% (IU)110%  36% (IV) 98% 23% (IW) 98% 23% (IX) 101%  18% (IY) 97%  8% (IZ)102%  21% (IAA) 98%  9% *Inhibitory rate at compound of 100 nmol/L

From the above tests, it is comfirmed that Compound (I) shows selectiveaffinity for the adenosine A_(2A) receptor.

Test Example 3

Therapeutic Effect of Combination of L-DOPA and the Thiazole Derivativeof the Present Invention or a Pharmaceutically Acceptable Salt Thereofon Common Marmoset that Developed Parkinson's Disease Symptom byTreatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Parkinson's disease is a disease based on the progressive degenerationand loss of dopaminergic neuron in substantia nigra-striatum. Inprimates, a treatment with MPTP, which is a dopamine neurotoxin, causesselective degeneration and loss of dopaminergic neuron in substantianigra-striatum and induces symptoms of akinesia, muscle rigidity and thelike. The primates treated with MPTP are known as the model ofParkinson's disease [Proceedings of the National Academy of Science USA,vol. 80, p. 4546 (1983)]. In addition, common marmoset belongs toHaplorhini and is known to show the symptoms of Parkinson's disease byMPTP, like other Haplorhini [Neuroscience Letter, vol. 57, p. 37(1985)]. 2 mg/kg of MPTP (Sigma-Aldrich Co. Ltd.) was subcutaneouslyadministered to the back of common marmoset (CLEA Japan, Inc.) once aday for 5 days, and 1-2 mg/kg of MPTP was additionally administeredsubcutaneously once or twice to the back about 3 weeks after firstadministration to prepare common marmoset exhibited chronic parkinsoniansymptoms (lower locomotor activity, bradykinesia, gait disturbance,abnormal postures, aless coordinated movements, decreased vocalizationand the like) (MPTP-treated marmoset), and the marmoset was used for thetest. The parkinsonian symptoms were judged using the index described ina previous report [Annales of Neurology, vol. 43, p. 507 (1998)]. Theobservation items and scores are shown in Table 2. All compounds wereused as a suspension in 0.5% MC400, 10% aqueous sucrose solution. Thesubject animal was placed in an observation cage (with locomotoractivity measuring apparatus) one day before the test compoundadministration for preconditioning to the environment. The symptoms ofParkinson's disease were continuously monitored through one-way mirrorand disability score was scored each 10 min for 6 hr.

TABLE 3 Disability Rating Scale Used in Common Marmoset score Items 0 12 3 4 Alertness Normal Reduced Sleepy — — Checking Present ReducedAbsent — — Movement Attention Normal Abnormal — — — Blinking PostureNormal abnormality of trunk, upper Grossly limb, lower limb, tail: each1 Abnormal point Balance/ Normal Impaired Unstable Falls — CoordinationReaction to Normal Reduced Slow Absent — stimuli Vocalization NormalReduced Absent — —

The locomotor activity was automatically measured using a computer by ameasuring apparatus with a photocell. When 2.5, 5.0, 7.5 and 10.0 mg/kgof L-DOPA (each containing 1/4 amount of dopa decarboxylase inhibitor(benserazide hydrochloride)) were each administered, the parkinsoniansymptoms in MPTP-treated marmoset decreased within increasement of thedosage. 1 mg/kg of compound (IC) and L-DOPA were simultaneouslyadministered orally. Co-administration of compound (IC) (1 mg/kg) withthe various doses of L-DOPA(2.5, 5.0, 7.5 and 10.0 mg/kg: eachcontaining ¼ amount of benserazide hydrochloride) prolonged theanti-parkinsonian activity of L-DOPA, and slso enhanced maximum effectsof L-DOPA alone. The time course of influence on motor disability scorewhen 1 mg/kg of compound (IC) and 10 mg/kg of L-DOPA were simultaneouslyadministered orally in combination is shown in FIG. 1. When 1 mg/kg ofcompound (IC) and 10 mg/kg of L-DOPA were simultaneously administeredorally in combination, the action expression time (on-time) increased ascompared to the treatment with 10 mg/kg of L-DOPA alone. In addition,the maximum improvement values of motor disability score when 1 mg/kg ofcompound (IC) and each dose of L-DOPA (2.5, 5.0, 7.5 and 10.0 mg/kg:each containing 1/4 amount of benserazide hydrochloride) weresimultaneously administered orally in combination, and when treated withL-DOPA alone are shown in FIG. 2. When 1 mg/kg of compound (IC) and eachdose of L-DOPA were simultaneously administered orally in combination,the intensity of the maximum improving maximum effects by each dose ofL-DOPA was enhanced.

From the above-mentioned test, Compound (I) is considered to haveeffects of enhancing the therapeutic effect of L-DOPA on Parkinson'sdisease and prolonging the duration of therapeutic effect of L-DOPA onParkinson's disease.

Test Example 4

Therapeutic Effect of Combination of L-DOPA and the Thiazole Derivativeor a Pharmaceutically Acceptable Salt Thereof of the Present Inventionin MPTP-Treated Common Marmoset that Developed Motor Complication

10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide hydrochloride)was administered by gavage to common marmoset that developed chronicparkinsonian symptoms by treatment with MPTP by the method described inTest Example 3 (MPTP-treated marmoset) twice a day at about 6 hrintervals. L-DOPA was repeatedly administered for more than 3 weeks toinduction of motor complication (dyskinesia symptom, wearing-offphenomenon, on-off fluctuation and the like) in MPTP-treated marmoset inaddition to parkinsonian symptoms, and the marmoset was used for thetest. The parkinsonian symptoms were judged using rating scale describedin a previous report [Annales of Neurology, vol. 43, p. 507 (1998)] asin Test Example 2. The locomotor activity was automatically measuredusing a computer by a measuring apparatus with a photocell. Allcompounds were used as a suspension in 0.5% MC400, 10% aqueous sucrosesolution. The subject animal was placed in an observation cage (withlocomotor activity measuring apparatus) one day before the test compoundadministration for preconditioning to the environment. The symptoms ofParkinson's disease were continuously monitored through one-way mirrorand disability score was scored each 10 min for 6 hr. When 2.5 mg/kg or10 mg/kg of L-DOPA (containing 2.5 or 0.625 mg/kg of benserazidehydrochloride) was administered, the parkinsonian symptoms inMPTP-treated marmoset decreased with the increasement of dosage. 1 mg/kgof compound (IC) and 2.5 mg/kg of L-DOPA were simultaneouslyadministered in combination by gavage. As a result, extension ofduration (on-time) of an anti-parkinsonian activities of L-DOPA (about50 min by treatment with L-DOPA 2.5 mg/kg alone, about 150 min bycombined administration of 1 mg/kg of compound (IC)), and enhanced thepotency (minimum disability score 5.33±0.80 by treatment with L-DOPA 2.5mg/kg alone, 3.83±0.17 by combined administration of 1 mg/kg of compound(IC)) were observed.

From the results of the above-mentioned Test Example 4, Compound (I) isconsidered to have an effect of suppressing wearing-off phenomenon,which is the side effect of L-DOPA.

Test Example 5

Influence of Combination of L-DOPA and the Thiazole Derivative or aPharmaceutically Acceptable Salt Thereof of the Present Invention onDyskinesia in MPTP-Treated Common Marmoset that Developed MotorComplication

10 mg/kg of L-DOPA (containing 2.5 mg/kg of benserazide hydrochloride)was administered to common marmoset that developed chronic parkinsoniansymptoms by treatment with MPTP by the method described in Test Example3 (MPTP-treated marmoset) twice a day at about 6 hr intervals. L-DOPAwas repeatedly administered for more than 3 weeks to induction of motorcomplication (dyskinesia symptom, wearing-off phenomenon, on-offfluctuation and the like) in MPTP-treated marmoset in addition toparkinsonian symptoms, and the marmoset was used for the test. Thedyskinesia severity was rating using the rating scale described in aprevious report [Annales of Neurology, vol. 43, p. 507 (1998)] as inTest Example 2. The evaluation items and scores are shown in Table 3.All compounds were used as a suspension of 0.5% MC400, 10% aqueoussucrose solution. The subject animal was placed in an observation cage(with locomotor activity measuring apparatus) one day before the testcompound administration for preconditioning to the environment. Thedyskinesia symptoms were observed through one-way mirror and scored each20 min for 6 hr.

TABLE 4 Dyskinesia Rating Scale Used in Common Marmoset evaluation itemscore Dyskinesia absent 0 Fleeting and rare dyskinetic postures mild 1More prominent abnormal movements, but not moderate 2 interferingsignificantly with normal behavior Continuous appearance of abnormalbehavior to marked 3 influence normal movement Mostly occupied byabnormal behavior, and no severe 4 normal animal movement

The locomotor activity was automatically measured using a computer by ameasuring apparatus with a photocell. When 1.25, 2.5, 5.0, 7.5 and 10mg/kg of L-DOPA (each containing 0.3125, 0.625, 1.25, 1.875 and 2.5mg/kg of benserazide hydrochloride, respectively) were eachadministered, dyskinesia was induced in MPTP-treated marmoset withincreasing dose of L-DOPA. A combination of 1 mg/kg of compound (IC) andL-DOPA was simultaneously administered orally. Combined administrationof 1 mg/kg of compound (IC) with the each doses of L-DOPA (1.25, 2.5,5.0, 7.5 and 10.0 mg/kg: each containing 1/4 amount of benserazidehydrochloride) did not exacerbate dyskinesia severity problematic foradministration of each dose of L-DOPA alone. When compound (IC) alonewas administered from 0.1 to 10 mg/kg, dyskinesia was not induced.

From the above-mentioned test, it was considered that Compound (I) doesnot exacerbate dyskinesia which is a side effect of L-DOPA. From theresults of Test Examples 3-5, it was considered that a combined use ofL-DOPA and a thiazole derivative such as Compound (I) and the like doesnot exacerbate dyskinesia which is a side effect of L-DOPA, but enhancea therapeutic effect of L-DOPA on Parkinson's disease (enhancement andprolongation of effect of L-DOPA).

From the aforementioned Test Examples 3-5, administration of Compound(I) or a pharmaceutically acceptable salt thereof is considered tosuppress or reduce side effects (e.g., wearing-off phenomenon, on-offfluctuation, dyskinesia or the like) of L-DOPA and/or dopamine agonisttherapy for Parkinson's disease or the like. Particularly, Compound (I)or a pharmaceutically acceptable salt thereof is considered to beeffective for the reducing wearing-off phenomenon in L-DOPA and/ordopamine agonist therapy.

Moreover, a combined use of Compound (I) or a pharmaceuticallyacceptable salt thereof and L-DOPA is considered to effectively treatparkinsonian symptoms (movement disorders relating to bradykinesia,gait, akinesia, or the like). Moreover, when Compound (I) or apharmaceutically acceptable salt thereof is used in combination withL-DOPA, an improving effect on parkinsonian symptoms and locomotoractivity becomes stronger than that by the use of L-DOPA alone. Thus, acombined use of Compound (I) or a pharmaceutically acceptable saltthereof and L-DOPA can reduce the dose of L-DOPA necessary for achievingthe same improvement level as a treatment with L-DOPA alone, and cansuppress or delay expression of side effects in the circulatory andgastrointestinal systems, as well as the onset of dyskinesia and motorcomplication due to L-DOPA.

The following more specifically describes the present invention by wayof Examples. It should be noted, however, that the scope of the presentinvention is not limited by the following Examples.

Example 1

Tablets having the following formulations are prepared according to theconventional manner. Compound (IA) (40 g), lactose (286.8 g), and potatostarch (60 g) are mixed, and then a 10% aqueous solution ofhydroxypropylcellulose (120 g) is added thereto. The resulting mixtureis kneaded according to the conventional manner, granulated, and driedto form granules for tableting. After adding thereto 1.2 g of magnesiumstearate followed by mixing, the mixture is punched with a tabletingmachine having a punch measuring 8 mm in diameter (Model RT-15; Kikusui)to obtain tablets (containing 20 mg of an active ingredient per tablet).

TABLE 5 Formulation Compound (IA) 20 mg lactose 143.4 mg potato starch30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6 mg 200 mg

Example 2

Tablets having the following formulation are prepared in the same manneras in Example 1.

TABLE 6 Formulation Compound (IB) 20 mg lactose 143.4 mg potato starch30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6 mg 200 mg

Example 3

Tablets having the following formulation are prepared in the same manneras in Example 1.

TABLE 7 Formulation Compound (IC) 20 mg lactose 143.4 mg potato starch30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6 mg 200 mg

Example 4

Tablets having the following formulation are prepared according to theconventional manner. Compound (IA) (40 g), L-DOPA (40 g), lactose (246.8g), and potato starch (60 g) are mixed, and then a 10% aqueous solutionof hydroxypropylcellulose (120 g) is added thereto. The resultingmixture is kneaded according to the conventional manner, granulated, anddried to form granules for tableting. After adding thereto 1.2 g ofmagnesium stearate followed by mixing, the mixture is punched with atableting machine having a punch measuring 8 mm in diameter (ModelRT-15; Kikusui) to obtain tablets (containing compound (IA) (20 mg) andL-DOPA (20 mg) per tablet).

TABLE 8 Formulation Compound (IA) 20 mg L-DOPA 20 mg lactose 123.4 mgpotato starch 30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6mg 200 mg

Example 5

Tablets having the following formulation are prepared in the same manneras in Example 4.

TABLE 9 Formulation Compound (IB) 20 mg L-DOPA 20 mg lactose 123.4 mgpotato starch 30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6mg 200 mg

Example 6

Tablets having the following formulation are prepared in the same manneras in Example 4.

TABLE 10 Formulation Compound (IC) 20 mg L-DOPA 20 mg lactose 123.4 mgpotato starch 30 mg hydroxypropylcellulose 6 mg magnesium stearate 0.6mg 200 mg

Example 7

Injections having the following formulation are prepared according tothe conventional manner. Compound (IA) (1 g) is added to distilled waterfor injection followed by mixing. After adjusting the pH of the mixtureto 7 by adding hydrochloric acid and a sodium hydroxide aqueous solutionthereto, the total volume is adjusted to 1,000 mL with distilled waterfor injection. The resulting mixture is aseptically charged into glassvials in 2-mL portions to obtain injections (containing 2 mg of anactive ingredient per vial).

TABLE 11 Formulation Compound (IA)   2 mg hydrochloric acid Appropriateamount aqueous sodium hydroxide solution Appropriate amount distilledwater for injection Appropriate amount 2.00 mL

Example 8

Injections having the following formulation are prepared in the samemanner as in Example 7.

TABLE 12 Formulation Compound (IB)   2 mg hydrochloric acid Appropriateamount aqueous sodium hydroxide solution Appropriate amount distilledwater for injection Appropriate amount 2.00 mL

Example 9

Injections having the following formulation are prepared in the samemanner as in Example 7.

TABLE 13 Formulation L-DOPA   2 mg hydrochloric acid Appropriate amountaqueous sodium hydroxide solution Appropriate amount distilled water forinjection Appropriate amount 2.00 mL

Example 10

Injections having the following formulation are prepared according tothe conventional manner. Compound IA (1 g) and L-DOPA (1 g) are added todistilled water for injection followed by mixing. After adjusting the pHof the mixture to 7 by adding hydrochloric acid and a sodium hydroxideaqueous solution thereto, the total volume is adjusted to 1,000 mL withdistilled water for injection. The resulting mixture is asepticallycharged into glass vials in 2-mL portions to obtain injections(containing compound (IA) (2 mg) and L-DOPA (2 mg) per vial).

TABLE 14 Formulation Compound (IA) 2 mg L-DOPA 2 mg hydrochloric acidAppropriate amount aqueous sodium hydroxide solution Appropriate amountdistilled water for injection Appropriate amount 2.00 mL  

Example 11

Injections having the following formulation are prepared in the samemanner as in Example 10.

TABLE 15 Formulation Compound (IC) 2 mg L-DOPA 2 mg hydrochloric acidAppropriate amount aqueous sodium hydroxide solution Appropriate amountdistilled water for injection Appropriate amount 2.00 mL  

Example 12N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl)-6-vinylpyridine-3-carboxamide(Compound IE)

step 1 Methyl 6-chloronicotinate (1.51 g, 8.79 mmol) was dissolved inDMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol),dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) andlithium chloride (554 mg, 13.1 mmol) were added and the mixture wasstirred at 100° C. for 2 hr. The mixture was allowed to cool to roomtemperature, and an aqueous potassium fluoride solution was addedthereto. The mixture was filtered through celite and the residue waswashed with ethyl acetate. To the obtained filtrate was added asaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=70:30) to givemethyl 6-vinylnicotinate (1.22 g, 85%) as a colorless transparent oil.

¹H NMR (CDCl₃, δppm): 3.95 (s, 3H), 5.63 (dd, J=1.1, 10.8 Hz, 1H), 6.35(dd, J=1.1, 17.4 Hz, 1H), 6.87 (dd, J=10.8, 17.4 Hz, 1H), 7.40 (d, J=8.2Hz, 1H), 8.25 (dd, J=2.1, 8.2 Hz, 1H), 9.15-9.18 (m, 1H).

step 2 Methyl 6-vinylnicotinate (491 mg, 2.97 mmol) obtained above wasdissolved in a 50% methanol aqueous solution (8 mL). Lithium hydroxidemonohydrate (276 mg, 6.57 mmol) was added thereto and the mixture wasstirred at room temperature for 1 hr. The mixture was cooled to 0° C.,then 3 mol/L hydrochloric acid (3 mL) was added, and the precipitatedsolid was collected by filtration to give 6-vinylnicotinic acid (309 mg,70%) as a white solid.

¹H NMR (DMSO-d₆, δppm): 5.61 (dd, J=1.5, 10.8 Hz, 1H), 6.37 (dd, J=1.5,17.4 Hz, 1H), 6.89 (dd, J=10.8, 17.4 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H),8.22 (dd, J=2.2, 8.2 Hz, 1H), 9.01 (d, J=2.2 Hz, 1H), 13.35 (brs, 1H).

step 3 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (301mg, 1.08 mmol) described in WO2005/063743 was dissolved in DMF (1.5 mL),EDC hydrochloride (412 mg, 2.15 mmol), DMAP (66 mg, 0.54 mmol) and6-vinylnicotinic acid (306 mg, 1.65 mmol) were added thereto, and themixture was stirred at 50° C. for 5 hr. The mixture was allowed to coolto room temperature, water and a saturated aqueous sodium hydrogencarbonate solution were added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=50:50), and recrystallized fromethanol-water to give Compound IE (1.22 g, 85%) as white crystals.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.11-3.25 (m, 1H), 3.51 (ddd,J=3.1, 11.4, 11.4 Hz, 2H), 4.02-4.11 (m, 2H), 5.71 (dd, J=0.8, 10.7 Hz,1H), 6.43 (dd, J=0.8, 17.5 Hz, 1H), 6.57 (dd, J=1.7, 3.8 Hz, 1H), 6.90(dd, J=10.7, 17.5 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.58 (dd, J=0.5, 1.7Hz, 1H), 7.84 (d, J=3.8 Hz, 1H), 8.21 (dd, J=2.4, 8.2 Hz, 1H), 9.13 (d,J=2.4 Hz, 1H), 9.84 (brs, 1H). ESIMS m/z: [M+H]⁺ 410.

Example 13N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl)acetamide(Compound IF)

2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (105 mg,0.377 mmol) described in WO2005/063743 was dissolved in DMF (2.0 mL),EDC hydrochloride (421 mg, 2.20 mmol), HOBt monohydrate (340 mg, 2.21mmol) and 3-pyridylacetic acid hydrochloride (370 mg, 2.14 mmol) wereadded thereto, and the mixture was stirred at 80° C. overnight. Themixture was allowed to cool to room temperature, and water and asaturated aqueous sodium hydrogen carbonate solution were added thereto.The precipitated solid was collected by filtration, and dried underreduced pressure. The obtained solid was purified by silica gel columnchromatography (hexane:ethyl acetate=50:50), and recrystallized fromethanol-water to give Compound IF (112 mg, 75%) as white crystals.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.05-3.16 (m, 1H), 3.45 (ddd,J=2.8, 11.4, 11.4 Hz, 2H), 3.81 (s, 2H), 3.97-4.06 (m, 2H), 6.54 (dd,J=1.8, 3.6 Hz, 1H), 7.32 (dd, J=7.8, 4.8 Hz, 1H), 7.52-7.54 (m, 1H),7.62-7.68 (m, 2H), 8.55-8.64 (m, 2H), 9.21 (s, 1H). APCIMS m/z: [M+H]⁺398.

Example 14N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-pyrrole-2-carboxamide(Compound IG)

In the same manner as in Example 13, Compound IG (86.0 mg, 65%) wasobtained as pale-brown crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (100 mg,0.360 mmol) described in WO2005/063743 and pyrrole-2-carboxylic acid(240 mg, 2.18 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.08-3.24 (m, 1H), 3.47 (ddd,J=2.7, 11.5, 11.5 Hz, 2H), 4.00-4.09 (m, 2H), 6.34-6.36 (m, 1H), 6.56(dd, J=1.8, 3.6 Hz, 1H), 6.86-6.88 (m, 1H), 7.06-7.10 (m, 1H), 7.55-7.57(m, 1H), 7.71 (dd, J=0.7, 3.7 Hz, 1H), 9.49 (brs, 1H), 9.65 (brs, 1H).APCIMS m/z: [M+H]⁺ 372.

Example 15N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-4-carboxamide(Compound IH)

In the same manner as in Example 13, Compound IH (97.6 mg, 63%) wasobtained as milky white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (102 mg,0.367 mmol) described in WO2005/063743 and indole-4-carboxylic acid (331mg, 2.05 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.17-3.28 (m, 1H), 3.50 (ddd,J=3.0, 11.2, 11.2 Hz, 2H), 4.02-4.11 (m, 2H), 6.58 (dd, J=1.7, 3.5 Hz,1H), 7.23-7.36 (m, 2H), 7.43-7.48 (m, 1H), 7.58-7.60 (m, 1H), 7.67 (dd,J=4.2, 7.7 Hz, 2H), 7.76 (dd, J=0.7, 3.5 Hz, 1H), 8.46 (brs, 1H), 9.70(brs, 1H). APCIMS m/z: [M+H]⁺ 422.

Example 16N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(morpholin-4-ylmethyl)pyridine-4-carboxamide(Compound II)

step 1 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (2.00g, 7.19 mmol)described in WO2005/063743 was dissolved in DMF (35 mL),EDC hydrochloride (5.50 g, 28.6 mmol), HOBt monohydrate (4.40 g, 28.8mmol) and 2-(chloromethyl)isonicotinic acid (4.93 g, 28.7 mmol) obtainedby the method described in WO03/043636 were added thereto, and themixture was stirred at 80° C. overnight. The mixture was allowed to coolto room temperature, and water and a saturated aqueous sodium hydrogencarbonate solution were added thereto. The precipitated solid wascollected by filtration, and dried under reduced pressure. The obtainedsolid was purified by silica gel column chromatography (hexane:ethylacetate=50:50) to give2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(700 mg, 23%) as a pale-brown solid.

¹H NMR (CDCl₃, δppm): 1.84-1.97 (m, 4H), 3.12-3.23 (m, 1H), 3.46-3.57(m, 2H), 4.02-4.11 (m, 2H), 4.75 (s, 2H), 6.52 (dd, J=3.6, 1.7 Hz, 1H),7.50 (dd, J=1.7, 0.7 Hz, 1H), 7.70 (dd, J=5.1, 1.7 Hz, 1H), 7.79 (dd,J=3.6, 0.7 Hz, 1H), 7.92-7.95 (m, 1H), 8.79 (dd, J=5.1, 0.7 Hz, 1H).

step 22-(Chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(70.0 mg, 0.162 mmol) obtained in step 1 was dissolved in acetonitrile(2.0 mL), then morpholine (70.0 μL, 2.15 mmol) was added thereto, andthe mixture was stirred with heating under reflux for 1 hr. The mixturewas allowed to cool to room temperature, water and a saturated aqueoussodium hydrogen carbonate solution were added thereto. The mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform:methanol=95:5), andreslurried with hexane-ethyl acetate to give Compound II (54.6 mg, 71%)as a pale-brown solid.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 2.51-2.59 (m, 4H), 3.10-3.24(m, 1H), 3.51 (ddd, J=3.0, 11.3, 11.3 Hz, 2H), 3.75-3.82 (m, 6H),4.01-4.13 (m, 2H), 6.59 (dd, J=1.8, 3.6 Hz, 1H), 7.60 (dd, J=0.7, 1.8Hz, 1H), 7.69 (dd, J=1.8, 5.1 Hz, 1H), 7.84 (dd, J=0.7, 3.6 Hz, 1H),7.93-7.95 (m, 1H), 8.82 (dd, J=0.7, 5.1 Hz, 1H). ESIMS m/z: [M+H]⁺ 483.

Example 17N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-methoxymethylpyridine-4-carboxamide(Compound IJ)

Under ice-cooling, 60% sodium hydride (10.0 mg, 0.250 mmol) wasdissolved in DMF (1.0 mL), methanol (110 μL, 2.72 mmol) was slowly addeddropwise thereto, and the mixture was stirred at 0° C. for 10 min. Then,2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(81.0 mg, 0.189 mmol) obtained in step 1 of Example 16, which wasdissolved in DMF (1.0 mL), was slowly added dropwise thereto, and themixture was stirred at room temperature for 5 hr. To the mixture wereadded water and a saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=50:50), andrecrystallized from ethanol-water to give Compound IJ (45.0 mg, 56%) aswhite crystals.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.14-3.23 (m, 1H), 3.52 (ddd,J=3.0, 11.2, 11.2 Hz, 2H), 3.53 (s, 3H), 4.02-4.18 (m, 2H), 4.65 (s,2H), 6.52 (dd, J=1.8, 3.6 Hz, 1H), 7.50 (d, J=1.1 Hz, 1H), 7.71 (dd,J=1.3, 5.1 Hz, 1H), 7.79 (d, J=3.6 Hz, 1H), 7.85 (s, 1H), 8.77 (d, J=5.1Hz, 1H), 10.41 (brs, 1H). APCIMS m/z: [M+H]⁺ 428.

Example 182-Ethoxymethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(Compound IK)

In the same manner as in Example 17, Compound IK (47.0 mg, 57%) wasobtained as white crystals from2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(80.0 mg, 0.185 mmol) and ethanol (200 μL, 3.54 mmol).

¹H NMR (CDCl₃, δppm): 1.36 (t, J=7.1 Hz, 3H), 1.80-2.01 (m, 4H),3.11-3.28 (m, 1H), 3.51 (ddd, J=3.2, 11.4, 11.4 Hz, 2H), 3.72 (q, J=7.1Hz, 2H), 4.00-4.12 (m, 2H), 4.73 (s, 2H), 6.58 (dd, J=1.7, 3.6 Hz, 1H),7.58 (dd, J=0.7, 1.7 Hz, 1H), 7.72 (dd, J=1.7, 5.0 Hz, 1H), 7.84 (dd,J=0.7, 3.6 Hz, 1H), 7.92 (dd, J=0.7, 1.7 Hz, 1H), 8.80 (d, J=5.0 Hz,1H), 9.95 (brs, 1H). APCIMS m/z: [M+H]⁺ 442.

Example 19N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-isopropoxymethylpyridine-4-carboxamide(Compound IL)

In the same manner as in Example 17, Compound IL (30.2 mg, 36%) wasobtained as white crystals from2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide(80.1 mg, 0.185 mmol) and 2-propanol (350 μL, 4.60 mmol).

¹H NMR (CDCl₃, δppm): 1.31 (d, J=6.0 Hz, 6H), 1.80-2.01 (m, 4H),3.15-3.22 (m, 1H), 3.51 (ddd, J=2.8, 11.4, 11.4 Hz, 2H), 3.78-3.86 (qq,J=6.0, 6.0 Hz, 1H), 4.01-4.11 (m, 2H), 4.73 (s, 2H), 6.58 (dd, J=1.8,3.6 Hz, 1H), 7.59 (dd, J=0.6, 1.8 Hz, 1H), 7.71 (dd, J=1.5, 5.1 Hz, 1H),7.85 (dd, J=0.4, 3.5 Hz, 1H), 7.93 (d, J=0.6 Hz, 1H), 8.79 (dd, J=0.4,5.1 Hz, 1H), 9.91 (brs, 1H). APCIMS m/z: [M+H]⁺ 456.

Example 20N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]furo[2,3-b]pyridine-5-carboxamide(Compound IM)

2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (125 mg,0.450 mmol) described in WO2005/063743 was dissolved in DMF (2.2 mL),EDC hydrochloride (173 mg, 0.900 mmol), HOBt monohydrate (138 mg, 0.900mmol) and furo[2,3-b]pyridine-5-carboxylic acid (147 mg, 0.900 mmol)obtained in the method described in Tetrahedron Letters, vol. 35, p.9355 (1994) were added thereto, and the mixture was stirred at 50° C.for 2 hr, then at 70° C. for 1 hr. To the mixture were added EDChydrochloride (173 mg, 0.900 mmol), HOBt monohydrate (138 mg, 0.900mmol) and furo[2,3-b]pyridine-5-carboxylic acid (147 mg, 0.900 mmol),and the mixture was stirred at 70° C. for 1.5 hr. The mixture was addedto water—a saturated aqueous sodium hydrogen carbonate solution (1:1)and the precipitated solid was collected by filtration and dried. Theobtained solid was purified by silica gel column chromatography(hexane:ethyl acetate=50:50), and recrystallized from ethanol-water togive Compound IM (81.2 mg, 43%).

¹H NMR (DMSO-d₆, δppm): 1.56-1.77 (m, 4H), 3.16-3.26 (m, 1H), 3.37-3.47(m, 2H), 3.87-3.92 (m, 2H), 6.71 (dd, J=1.9, 3.5 Hz, 1H), 7.21 (d, J=2.4Hz, 1H), 7.45 (dd, J=0.9, 3.5 Hz, 1H), 7.91 (dd, J=0.9, 1.9 Hz, 1H),8.27 (d, J=2.4 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H).ESIMS m/z: [M+H]⁺ 424.

Example 21N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-2-yl)acetamide(Compound IN)

In the same manner as in step 3 of Example 12, Compound IN (125 mg, 58%)was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (154 mg,0.553 mmol) described in WO2005/063743 and 2-pyridylacetic acidhydrochloride (196 mg, 1.13 mmol).

¹H NMR (CDCl₃, δppm): 1.78-1.95 (m, 4H), 3.01-3.21 (m, 1H), 3.47 (ddd,J=2.6, 11.4, 11.4 Hz, 2H), 3.98-4.09 (m, 2H), 4.03 (s, 2H), 6.57 (dd,J=1.8, 3.6 Hz, 1H), 7.25-7.34 (m, 2H), 7.59 (dd, J=0.7, 1.8 Hz, 1H),7.70 (dd, J=0.7, 3.5 Hz, 1H), 7.74 (ddd, J=1.8, 7.7, 7.7 Hz, 1H),8.69-8.73 (m, 1H), 12.09 (brs, 1H). APCIMS m/z: [M+H]⁺ 398.

Example 22N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-methoxypyridine-3-carboxamide(Compound IO)

In the same manner as in step 3 of Example 12, Compound IO (121 mg, 54%)was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (150 mg,0.539 mmol) described in WO2005/063743 and 6-methoxynicotinic acid (101mg, 0.659 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.10-3.25 (m, 1H), 3.51 (ddd,J=2.9, 11.4, 11.4 Hz, 2H), 4.02-4.11 (m, 2H), 4.04 (s, 3H), 6.55 (dd,J=1.7, 3.5 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 7.53-7.57 (m, 1H), 7.83 (dd,J=0.6, 3.5 Hz, 1H), 8.10 (dd, J=2.6, 8.8 Hz, 1H), 8.77 (dd, J=0.6, 2.6Hz, 1H), 9.93 (brs, 1H). APCIMS m/z: [M+H]⁺ 414.

Example 23N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]quinoline-3-carboxamide(Compound IP)

In the same manner as in step 3 of Example 12, Compound IP (178 mg, 76%)was obtained as pale-yellow crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151 mg,0.543 mmol) described in WO2005/063743 and quinoline-3-carboxylic acid(142 mg, 0.820 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.15-3.25 (m, 1H), 3.52 (ddd,J=2.9, 11.4, 11.4 Hz, 2H), 4.06-4.10 (m, 2H), 6.47 (dd, J=1.7, 3.5 Hz,1H), 7.47 (dd, J=0.7, 1.6 Hz, 1H), 7.66-7.74 (m, 2H), 7.87-7.95 (m, 2H),8.20 (dd, J=0.9, 8.4 Hz, 1H), 8.71 (d, J=1.8 Hz, 1H), 9.43 (d, J=2.4 Hz,1H), 10.55 (s, 1H). APCIMS m/z: [M+H]⁺ 434.

Example 24N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-5,6-dimethylpyridine-3-carboxamide(Compound IQ)

step 1 5,6-Dimethylpyridine-3-carbonitrile (502 mg, 3.79 mmol) obtainedby the method described in J. Heterocyclic Chem., vol. 24, p. 351 (1987)was suspended in 70% aqueous ethanol (4.5 mL), sodium hydroxide (444 mg,11.1 mmol) was added thereto, and the mixture was stirred with heatingunder reflux for 3 hr. The mixture was ice-cooled to 0° C., and 6 mol/Lhydrochloric acid (1.9 ml) was added thereto. The mixture wasconcentrated under reduced pressure and the obtained residue wassuspended in chloroform-methanol. The inorganic salt was removed byfiltration, and the obtained filtrate was concentrated under reducedpressure to give 5,6-dimethylpyridine-3-carboxylic acid (569 mg, 99%) asa pale-pink crude solid.

¹H NMR (DMSO-d₆, δppm): 2.23 (s, 3H), 2.39 (s, 3H), 7.83 (d, J=1.7 Hz,1H), 8.64 (d, J=1.7 Hz, 1H).

step 2 In the same manner as in step 3 of Example 12, Compound IQ (112mg, 49%) was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151 mg,0.550 mmol) described in WO2005/063743 and5,6-dimethylpyridine-3-carboxylic acid (166 mg, 1.10 mmol) obtainedabove.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 2.34 (s, 3H), 2.59 (s, 3H),3.12-3.23 (m, 1H), 3.51 (ddd, J=2.9, 11.3, 11.3 Hz, 2H), 4.04-4.09 (m,2H), 6.49 (dd, J=2.0, 3.6 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.79 (dd,J=0.5, 3.5 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H).ESIMS m/z: [M+H]⁺ 412.

Example 255-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide(Compound IR)

In the same manner as in step 3 of Example 12, Compound IR (145 mg, 65%)was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151 mg,0.543 mmol) described in WO2005/063743 and 5-ethylnicotinic acid (128mg, 0.814 mmol).

¹H NMR (CDCl₃, δppm): 1.32 (t, J=7.6 Hz, 3H), 1.83-2.01 (m, 4H), 2.77(q, J=7.6 Hz, 2H), 3.11-3.26 (m, 1H), 3.51 (ddd, J=2.9, 11.4, 11.4 Hz,2H), 4.01-4.11 (m, 2H), 6.54 (dd, J=1.8, 3.6 Hz, 1H), 7.51-7.53 (m, 1H),7.80 (dd, J=0.7, 3.6 Hz, 1H), 8.03-8.06 (m, 1H), 8.70 (d, J=2.0 Hz, 1H),8.99 (d, J=2.0 Hz, 1H), 10.24 (brs, 1H). ESIMS m/z: [M+H]⁺ 412.

Example 26N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxamide(Compound IS)

step 1 Sodium hydride (2.06 g, 51.5 mmol) was suspended in diethyl ether(40 mL), and methanol (2.1 ml, 51.8 mmol) was added slowly at −5° C.thereto. To the mixture was added ethanol (6 mL), and the mixture wasstirred at room temperature for 5 min, and cooled to 0° C. A mixture oftetrahydro-4H-pyran-4-one (4.61 mL, 49.9 mmol) and ethyl formate (4.11ml, 51.1 mmol) was slowly added thereto. The mixture was stirred at roomtemperature for 2 hr, and the resultant product was extracted with water(30 ml) (aqueous solution A).

Then, an aqueous piperidine-acettic acid solution prepared by dissolvingacetic acid (1.5 mL) in water (3.5 mL) and adding piperidine (2.6 mL)thereto, and 2-cyanoacetamide (4.62 g, 54.9 mmol) were added to theabove-mentioned aqueous solution A, and the mixture was stirred withheating under reflux for 4 hr. To the mixture was added acetic acid (3.6mL) and, after cooling 0° C., the precipitated solid was collected byfiltration to give2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (1.72g, 20%) as a white solid.

¹H NMR (CDCl₃, δppm): 2.89 (t, J=5.6 Hz, 2H), 3.99 (t, J=5.6 Hz, 2H),4.54 (s, 2H), 7.59 (s, 1H). APCIMS m/z: [M−H]⁻ 175.

step 2 2-Oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile(2.50 g, 14.4 mmol) obtained in step 1 was dissolved in phosphorylchloride (20 mL), and the mixture was stirred with heating under refluxfor 4 hr. The mixture was allowed to cool to room temperature, andslowly added to a saturated aqueous sodium hydrogen carbonate solutionat 0° C., then the mixture was extracted with chloroform. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane:ethylacetate=50:50) to give2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.85 g,66%) as a white solid.

¹H NMR (CDCl₃, δppm): 3.07 (t, J=5.8 Hz, 2H), 4.07 (t, J=5.8 Hz, 2H),4.75-4.76 (m, 2H), 7.63 (s, 1H).

step 3 2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile(1.77 g, 9.09 mmol) obtained in step 2 was dissolved in ethanol (30 mL),acetic acid (9 mL) and zinc (2.60 g) were added thereto, and the mixturewas stirred with heating under reflux for 4 hr. The mixture was allowedto cool to room temperature, then filtered through celite, and thefiltrate was concentrated under reduced pressure. To the obtainedresidue was added a saturated aqueous sodium hydrogen carbonate solutionand the mixture was extracted with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=50:50) to give7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.06 g, 73%) as awhite solid.

¹H NMR (CDCl₃, δppm): 3.10 (t, J=5.8 Hz, 2H), 4.10 (t, J=5.8 Hz, 2H),4.79 (s, 2H), 7.59 (d, J=1.7 Hz, 1H), 8.71 (d, J=1.7 Hz, 1H). APCIMSm/z: [M+H]⁺ 161.

step 4 In the same manner as in step 1 of Example 24,7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid (318 mg, 47%) wasobtained as a white solid from7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (609 mg, 3.80 mmol)obtained above.

¹H NMR (DMSO-d₆, δppm): 2.86 (t, J=5.8 Hz, 2H), 3.95 (t, J=5.8 Hz, 2H),4.70 (s, 2H), 7.80 (d, J=1.7 Hz, 1H), 8.76 (d, J=1.7 Hz, 1H). ESIMS m/z:[M−H]⁻ 178.

step 5 In the same manner as in step 3 of Example 12, Compound IS (178mg, 74%) was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (152 mg,0.546 mmol) described in WO2005/063743 and7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid (432 mg, 2.00mmol) obtained above.

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.10 (t, J=5.6 Hz, 2H),3.13-3.24 (m, 1H), 3.51 (ddd, J=2.8, 11.4, 11.4 Hz, 2H), 4.03-4.14 (m,4H), 4.79 (s, 2H), 6.50 (dd, J=1.7, 3.6 Hz, 1H), 7.46 (dd, J=0.6, 1.7Hz, 1H), 7.78 (dd, J=0.6, 3.6 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 8.94 (d,J=2.2 Hz, 1H), 10.58 (s, 1H). ESIMS m/z: [M+H]⁺ 440.

Example 27N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide(Compound IT)

step 1 6,7-Dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (901 mg, 6.25mmol) obtained by the method described in J. Heterocyclic Chem., vol.24, p. 351 (1987) was suspended in 6 mol/L hydrochloric acid (9 mL), andthe mixture was stirred with heating under reflux for 5 hr. The mixturewas ice-cooled to 0° C., and the precipitated solid was collected byfiltration to give 6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylicacid hydrochloride (543 mg, 44%) as a pale-brown solid.

¹H NMR (DMSO-d₆, δppm): 2.16 (tt, J=7.4, 7.8 Hz, 2H), 3.02 (t, J=7.4 Hz,2H), 3.10 (t, J=7.8 Hz, 2H), 8.34 (s, 1H), 8.92 (s, 1H).

step 2 In the same manner as in step 3 of Example 12, Compound IT (134mg, 58%) was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (152 mg,0.546 mmol) described in WO2005/063743 and6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid hydrochloride(165 mg, 0.827 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 1.78-2.01 (m, 4H), 2.16-2.28 (m, 2H), 3.01 (t,J=7.6 Hz, 2H), 3.10 (t, J=7.7 Hz, 2H), 3.11-3.25 (m, 1H), 3.51 (ddd,J=3.0, 11.4, 11.4 Hz, 2H), 4.00-4.10 (m, 2H), 6.52 (dd, J=1.8, 3.6 Hz,1H), 7.51 (dd, J=0.7, 1.7 Hz, 1H), 7.80 (dd, J=0.7, 3.6 Hz, 1H),7.95-8.00 (m, 1H), 8.87-8.91 (m, 1H), 10.20 (brs, 1H). ESIMS m/z: [M+H]⁺424.

Example 28N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-2-carboxamide(Compound IU)

In the same manner as in Example 13, Compound IU (97.5 mg, 63%) wasobtained as pale-brown crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (102 mg,0.366 mmol) described in WO2005/063743 and indole-2-carboxylic acid (350mg, 2.17 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 3.10-3.24 (m, 1H), 3.50 (ddd,J=2.7, 11.5, 11.5 Hz, 2H), 4.01-4.11 (m, 2H), 6.59 (dd, J=1.7, 3.5 Hz,1H), 7.14 (dd, J=0.9, 2.2 Hz, 1H), 7.19-7.25 (m, 1H), 7.36-7.43 (m, 1H),7.46-7.52 (m, 1H), 7.60 (dd, J=0.7, 1.7 Hz, 1H), 7.72-7.77 (m, 1H), 7.83(dd, J=0.7, 3.5 Hz, 1H), 9.21 (brs, 1H), 9.66 (brs, 1H). APCIMS m/z:[M+H]⁺ 422.

Example 296-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide(Compound IV)

Compound IE (90.0 mg, 0.220 mmol) obtained in Example 12% was dissolvedin ethanol (10 mL) under an argon atmosphere, 10% palladium carbon(10%-Pd/C; containing water) (88.9 mg) was added thereto, and mixturewas stirred at room temperature overnight under a hydrogen atmosphere.The mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby preparative thin layer chromatography (hexane:ethyl acetate=30:70),and recrystallized from ethanol-water to give Compound IV (70.0 mg, 77%)as white crystals.

¹H NMR (CDCl₃, δppm): 1.36 (t, J=7.6 Hz, 3H), 1.80-2.01 (m, 4H), 2.94(q, J=7.6 Hz, 2H), 3.11-3.27 (m, 1H), 3.51 (ddd, J=3.0, 11.3, 11.3 Hz,2H), 3.99-4.13 (m, 2H), 6.54 (dd, J=1.7, 3.5 Hz, 1H), 7.35 (d, J=8.1 Hz,1H), 7.52 (dd, J=0.7, 1.7 Hz, 1H), 7.81 (dd, J=0.7, 3.6 Hz, 1H), 8.15(dd, J=2.2, 8.2 Hz, 1H), 9.08 (d, J=2.2 Hz, 1H), 10.13 (brs, 1H). ESIMSm/z: [M+H]⁺ 412.

Example 30N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-propylpyridine-3-carboxamide(Compound IW)

step 1 In the same manner as in step 1 of Example 12, methyl6-(1-propenyl)nicotinate (327 mg, 37%) was obtained as a colorlesstransparent oil from methyl 6-chloronicotinate (862 mg, 6.48 mmol) andallyltributyltin (2.20 ml, 7.09 mmol).

¹H NMR (CDCl₃, δppm): 1.97 (dd, J=1.7, 6.8 Hz, 3H), 3.95 (s, 3H), 6.55(dq, J=1.7, 15.7 Hz, 1H), 6.92 (dq, J=6.8, 15.7 Hz, 1H), 7.25-7.30 (m,1H), 8.19 (dd, J=2.2, 8.2 Hz, 1H), 9.11 (dd, J=0.5, 2.2 Hz, 1H).

step 2 In the same manner as in step 2 of Example 12,6-(1-propenyl)nicotinic acid (251 mg, 84%) was obtained as milk-whitecrystals from methyl 6-(1-propenyl)nicotinate (326 mg, 1.84 mmol)obtained above.

¹H NMR (DMSO-d₅, δppm): 1.91 (dd, J=1.8, 6.8 Hz, 3H), 6.58 (dq, J=1.8,15.5 Hz, 1H), 6.91 (dq, J=6.8, 15.5 Hz, 1H), 7.48 (dd, J=0.5, 8.3 Hz,1H), 8.15 (dd, J=2.2, 8.3 Hz, 1H), 8.95 (dd, J=0.5, 2.2 Hz, 1H), 13.24(brs, 1H). ESIMS m/z: [M+H]⁺ 164.

step 3 In the same manner as in step 3 of Example 12,N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)pyridine-3-carboxamide(125 mg, 33%) was obtained as white crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (257 mg,0.908 mmol) described in WO2005/063743 and 6-(1-propenyl)nicotinic acid(251 mg, 1.26 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 1.82-1.96 (m, 4H), 2.01 (dd, J=1.4, 6.8 Hz, 3H),3.12-3.23 (m, 1H), 3.52 (ddd, J=3.0, 11.2, 11.2 Hz, 2H), 4.02-4.11 (m,2H), 6.54-6.62 (m, 2H), 7.00 (dd, J=6.8, 15.5 Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.55 (dd, J=0.8, 1.6 Hz, 1H), 7.82 (d, J=3.6 Hz, 1H), 8.15 (dd,J=2.4, 8.3 Hz, 1H), 9.08 (d, J=2.4 Hz, 1H), 10.00 (brs, 1H). ESIMS m/z:[M+H]⁺ 424.

step 4 In the same manner as in Example 29, the title Compound IW (96.0mg, 76%) was obtained as white crystals fromN-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)pyridine-3-carboxamide(125 mg, 0.296 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 1.00 (t, J=7.3 Hz, 3H), 1.75-1.97 (m, 6H), 2.88(t, J=7.6 Hz, 2H), 3.13-3.24 (m, 1H), 3.51 (ddd, J=3.1, 11.4, 11.4 Hz,2H), 4.02-4.11 (m, 2H), 6.55 (dd, J=1.8, 3.6 Hz, 1H), 7.33 (d, J=8.2 Hz,1H), 7.53-7.55 (m, 1H), 7.81 (d, J=3.6 Hz, 1H), 8.15 (dd, J=2.5, 8.2 Hz,1H), 9.09 (d, J=2.1 Hz, 1H), 10.14 (s, 1H). ESIMS m/z: [M+H]⁺ 426.

Example 31N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxamide(Compound IX)

step 1 In the same manner as in step 1 of Example 26,2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile(3.06 g, 37%) was obtained as a pale-yellow solid fromtetrahydro-4H-thiopyran-4-one (5.00 g, 43.0 mmol).

¹H NMR (CDCl₃, δppm): 2.93 (t, J=6.0 Hz, 2H), 3.11 (t, J=6.0 Hz, 2H),3.58 (s, 2H), 7.67 (s, 1H), 13.4 (brs, 1H).

step 2 In the same manner as in step 2 of Example 26,2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (1.75g, 58%) was obtained from2-oxo-1,5,7,8-tetrahydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile(2.78 g, 14.4 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 3.01 (t, J=6.1 Hz, 2H), 3.27 (t, J=6.1 Hz, 2H),3.78 (s, 2H), 7.71 (s, 1H).

step 3 In the same manner as in step 3 of Example 26,7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (804 mg, 55%)was obtained from2-chloro-7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (1.75g, 8.31 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 3.04 (t, J=6.2 Hz, 2H), 3.30 (t, J=6.2 Hz, 2H),3.81 (s, 2H), 7.68 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H).

step 4 In the same manner as in step 1 of Example 27,7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxylic acid hydrochloride(901 mg, 78%) was obtained from7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carbonitrile (874 mg, 4.96mmol) obtained above.

¹H NMR (DMSO-d₆, δppm): 3.01 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.2 Hz, 2H),3.96 (s, 2H), 8.27-8.36 (m, 1H), 8.92 (d, J=1.8 Hz, 1H). ESIMS m/z:[M−H]⁻ 194.

step 5 In the same manner as in step 3 of Example 12, Compound IX (79.0mg, 68%) was obtained as pale-brown crystals from2-amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (70.7 mg,0.254 mmol) described in WO2005/063743 and7,8-dihydro-5H-thiopyrano[4,3-b]pyridine-3-carboxylic acid hydrochloride(90.9 mg, 0.392 mmol) obtained above.

¹H NMR (CDCl₃, δppm): 1.81-2.01 (m, 4H), 3.05 (t, J=6.2 Hz, 2H),3.15-3.22 (m, 1H), 3.33 (t, J=6.0 Hz, 2H), 3.51 (ddd, J=2.9, 11.4, 11.4Hz, 2H), 3.83 (s, 2H), 4.03-4.10 (m, 2H), 6.53 (dd, J=1.8, 3.5 Hz, 1H),7.51 (dd, J=0.7, 1.8 Hz, 1H), 7.81 (dd, J=0.7, 3.5 Hz, 1H), 7.94-7.96(m, 1H), 8.95 (d, J=2.2 Hz, 1H). ESIMS m/z: [M+H]⁺ 456.

Example 325-Acetyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-methylpyridine-3-carboxamide(Compound IY)

step 1 In the same manner as in step 2 of Example 12,5-acetyl-6-methylpyridine-3-carboxylic acid (462 mg, quantitative) wasobtained as a yellow solid from ethyl5-acetyl-6-methylpyridine-3-carboxylate (561 mg, 2.71 mmol) obtained bythe method described in Synthesis, vol. 5, p. 400 (1986).

¹H NMR (DMSO-d₆, δppm): 2.63 (s, 3H), 2.66 (s, 3H), 8.54 (d, J=2.0 Hz,1H), 9.01 (d, J=2.0 Hz, 1H).

step 2 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (71.2mg, 0.256 mmol) described in WO2005/063743 was dissolved in DMF (0.5ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) (262 mg, 0.510 mmol), diisopropylethylamine (DIPEA) (150 μL,0.860 mmol) and 5-acetyl-6-methylpyridine-3-carboxylic acid (93.2 mg,0.520 mmol) obtained above were added thereto, and the mixture wasstirred at 80° C. overnight. The mixture was allowed to cool to roomtemperature, water and a saturated aqueous sodium hydrogen carbonatesolution were added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=50:50), and reslurried withethanol-water to give Compound IY (87.4 mg, 77%) as a pale-yellow solid.

¹H NMR (CDCl₃, δppm): 1.81-2.01 (m, 4H), 2.67 (s, 3H), 2.86 (s, 3H),3.13-3.23 (m, 1H), 3.51 (ddd, J=2.9, 11.4, 11.4 Hz, 2H), 4.03-4.10 (m,2H), 6.56 (dd, J=1.7, 3.5 Hz, 1H), 7.55 (dd, J=0.6, 1.7 Hz, 1H), 7.82(d, J=0.6, 3.5 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H).ESIMS m/z: [M+H]⁺ 440.

Example 335-Ethyl-N-[4-(3-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide(Compound IZ)

In the same manner as in step 3 of Example 12, Compound IZ (177 mg, 79%)was obtained as white crystals from2-amino-4-(3-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (151 mg,0.541 mmol) obtained by the method described in WO2005/063743 and5-ethylnicotinic acid (249 mg, 1.64 mmol).

¹H NMR (CDCl₃, δppm): 1.34 (t, J=7.6 Hz, 3H), 1.80-2.01 (m, 4H), 2.80(q, J=7.6 Hz, 2H), 3.11-3.18 (m, 1H), 3.51 (ddd, J=2.8, 11.4, 11.4 Hz,2H), 4.01-4.10 (m, 2H), 7.01 (dd, J=0.7, 1.8 Hz, 1H), 7.45-7.48 (m, 1H),8.10-8.13 (m, 1H), 8.63 (dd, J=0.7, 1.5 Hz, 1H), 8.71-8.76 (m, 1H),9.02-9.05 (m, 1H). ESIMS m/z: [M+H]⁺ 412.

Example 34N-[4-(3-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide(Compound IAA)

In the same manner as in step 3 of Example 12, Compound IAA (71.1 mg,39%) was obtained as white crystals from2-amino-4-(3-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (120 mg,0.432 mmol) and 6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acidhydrochloride (172 mg, 0.870 mmol).

¹H NMR (CDCl₃, δppm): 1.80-2.01 (m, 4H), 2.18-2.30 (m, 2H), 3.03-3.20(m, 5H), 3.52 (ddd, J=2.9, 11.3, 11.3 Hz, 2H), 4.01-4.10 (m, 2H), 7.03(dd, J=0.6, 2.0 Hz, 1H), 7.48 (dd, J=1.7, 1.7 Hz, 1H), 8.08-8.10 (m,1H), 8.68-8.70 (m, 1H), 8.95-8.97 (m, 1H). ESIMS m/z: [M+H]⁺ 424.

Reference Example 1

Compounds (IA)-(ID) were obtained according to the method described inWO2005/063743.

INDUSTRIAL APPLICABILITY

The present invention can be utilized for the treatment and/orprophylaxis of, for example, movement disorders (specifically, forexample, extrapyramidal syndrome, side effects of L-DOPA and/or dopamineagonist therapy and the like), or the treatment and/or prophylaxis ofParkinson's disease.

EXPLANATION OF SYMBOLS

-   -   ◯ combination of solvent and L-DOPA    -    combination of compound (IC) and L-DOPA

1-11. (canceled)
 12. A pharmaceutical composition comprising: (a) athiazole derivative represented by formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and(b) L-DOPA and/or a dopamine agonist.
 13. The pharmaceutical compositionaccording to claim 12, wherein R¹ is phenyl, pyridyl, pyrimidinyl,5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, each of which isoptionally substituted by 1 to 3 substituents selected from a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, methoxy andethoxy, or a pharmaceutically acceptable salt thereof.
 14. Thepharmaceutical composition according to claim 13, wherein R² is pyridyl,or a pharmaceutically acceptable salt thereof.
 15. The pharmaceuticalcomposition according to claim 13, wherein R² is tetrahydropyranyl, or apharmaceutically acceptable salt thereof.
 16. The pharmaceuticalcomposition according to claim 12, wherein the thiazole derivative isrepresented by formulas (IA)-(IAA):

or a pharmaceutically acceptable salt thereof. 17-22. (canceled)
 23. Akit, comprising: (a) a first component comprising a thiazole derivativerepresented by formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and(b) a second component comprising L-DOPA and/or a dopamine agonist. 24.The kit according to claim 23, wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, or a pharmaceutically acceptable salt thereof.
 25. The kitaccording to claim 24, wherein R² is pyridyl, or a pharmaceuticallyacceptable salt thereof.
 26. The kit according to claim 24, wherein R²is tetrahydropyranyl, or a pharmaceutically acceptable salt thereof. 27.The kit according to claim 23, wherein the thiazole derivative isrepresented by one of formulas (IA)-(IAA):

or a pharmaceutically acceptable salt thereof.
 28. A method of treatingand/or preventing progression of a movement disorder, comprising thesteps of: administering to a patient an effective amount of a thiazolederivative represented by formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof. 29.The method according to claim 28, wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, or a pharmaceutically acceptable salt thereof.
 30. Themethod according to claim 29, wherein R² is pyridyl, or apharmaceutically acceptable salt thereof.
 31. The method according toclaim 29, wherein R² is tetrahydropyranyl, or a pharmaceuticallyacceptable salt thereof.
 32. The method according to claim 28, whereinthe thiazole derivative is represented by any one of formulas(IA)-(IAA):

or a pharmaceutically acceptable salt thereof.
 33. The method accordingto claim 28, wherein the movement disorder is extrapyramidal syndrome.34. The method according to claim 28, wherein the movement disorder isbradykinesia, gait disturbance, dystonia, dyskinesia or tardivedyskinesia.
 35. The method according to claim 28, wherein the movementdisorder is a side effect of L-DOPA and/or dopamine agonist therapy. 36.The method according to claim 35, wherein the side effect is a motorcomplication.
 37. The method according to claim 36, wherein the motorcomplication is wearing-off phenomenon.
 38. The method according toclaim 36, wherein the motor complication is on-off fluctuation.
 39. Amethod of treating and/or preventing progression of Parkinson's disease,comprising the steps of: administering to a patient simultaneously orseparately at an interval (a) an effective amount of a thiazolederivative represented by formula (I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and(b) an effective amount of L-DOPA and/or a dopamine agonist.
 40. Themethod according to claim 39, wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, or a pharmaceutically acceptable salt thereof.
 41. Themethod according to claim 40, wherein R² is pyridyl, or apharmaceutically acceptable salt thereof.
 42. The method according toclaim 40, wherein R² is tetrahydropyranyl, or a pharmaceuticallyacceptable salt thereof.
 43. The method according to claim 39, whereinthe thiazole derivative is represented by any one of formulas(IA)-(IAA):

or a pharmaceutically acceptable salt thereof. 44-54. (canceled)
 55. Acompound represented by any one of the following formulas (IE)-(IAA), ora pharmaceutically acceptable salt thereof:


56. A combination of: (a) a thiazole derivative represented by formula(I)

wherein R¹ represents aryl, aralkyl, an aromatic heterocyclic group,aromatic heterocycle-alkyl, aliphatic heterocycle-alkyl ortetrahydropyranyloxy, each of which is optionally substituted by 1 to 3substituents selected from the group consisting of halogen; lower alkyloptionally substituted by lower alkoxy or morpholino; lower alkoxy;lower alkanoyl; and vinyl, and R² represents pyridyl ortetrahydropyranyl, or a pharmaceutically acceptable salt thereof, and(b) L-DOPA and/or a dopamine agonist, for use in the treatment and/orprophylaxis of Parkinson's disease.
 57. The combination according toclaim 56, wherein (a) and (b) are administered simultaneously.
 58. Thecombination according to claim 56, wherein R¹ is phenyl, pyridyl,pyrimidinyl, 5,6-dihydro-2H-pyridylmethyl or tetrahydropyranyloxy, eachof which is optionally substituted by 1 to 3 substituents selected froma fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, methoxyand ethoxy, or a pharmaceutically acceptable salt thereof.
 59. Thecombination according to claim 58, wherein R² is pyridyl, or apharmaceutically acceptable salt thereof.
 60. The combination accordingto claim 58, wherein R² is tetrahydropyranyl, or a pharmaceuticallyacceptable salt thereof.
 61. The combination according to claim 56,wherein the thiazole derivative is represented by any one of formulas(IA)-(IAA):

or a pharmaceutically acceptable salt thereof. 62-73. (canceled)
 74. Thecombination according to claim 56, wherein (a) and (b) are administeredseparately at an interval. 75-78. (canceled)